NZ530004A

NZ530004A - Pyrrolidine derivatives as factor Xa inhibitors that have oral bioavailability and PK profiles suitable for acute and chronic thrombotic conditions

Info

Publication number: NZ530004A
Application number: NZ530004A
Authority: NZ
Inventors: Chuen Chan; Julie Nicole Hamblin; Henry Anderson Kelly; Nigel Paul King; Andrew Mcmurtrie Mason; Vipulkumar Kantibhai Patel; Stefan Senger; Gita Punjabhai Shah; Nigel Stephen Watson; Helen Elisabeth Weston; Caroline Whitworth; Robert John Young
Original assignee: Glaxo Group Ltd
Priority date: 2001-06-08
Filing date: 2002-06-06
Publication date: 2005-08-26
Also published as: CN1538955A; EP1395553B1; KR100877245B1; CA2449629A1; PT1395553E; DE60203006D1; CO5540285A2; US7429587B2; US7517879B2; HUP0400156A2; ATE289294T1; CN1256324C; AU2002311451B2; KR20040004706A; US20070155745A1; JP2004537530A; IL159195A0; NO326689B1; DK1395553T3; TWI298719B

Abstract

Described are compounds of formula (I) and processes for their preparation, pharmaceutical compositions containing them and their use in the amelioration of a clinical condition for which a Factor Xa inhibitor is indicated. wherein: R1 represents hydrogen, -C1-6alkyl, -C3-6alkenyl, or a group X-W, wherein X represents -C1-3alkylene and W represents -CN, -CO2H, -CONRbRc, -OCI-6alkyl, -CO2CI-6alkyl, phenyl or a 5-or 6-membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one or more substituents selected from: -C1-3alkyl, -C1-3alkoxy, -C1-3alkylOH, halogen, -CN, -CF3, -NH2, -CO-H and OH; R2 and R3 is -C1-3alkyl or -CF3 and the other is hydrogen; Rb and Rc independently represent hydrogen or-C1-3alkyl; A represents a group selected from: Z represents one or two optional substituents independently selected from halogen and OH, W represents an optional substituent -C1-3alkyl, elk represents C2-3alkylene or C2-3alkenylene, T represents a heteroatom selected from O, S or N; B represents one or more optional substituents on ring carbon atoms selected from: (i) one or more substituents selected from -CF3, -F, -CO-H, -C1-6alkyl, -C1-6alkylOH, -(C1-3alkyl)NRbRc, -(C0 3alkyl)CONRbRc and -(C0-3alkyl)CO2C1-3alkyl, -CONHC2-3alkylOH, CH2NHC2-3alkylOH, -CH2OC1-3alkyl and -CH2SO2C1-3alkyl ; (ii) a group-Y-R Y represents -C1-3alkylene-, -CO-, -C1-3alkylNH-, -C1-3alkylNHCO-, -C1-3alkylNHSO2-, CH2NHSO2CH2-or a direct link, Re represents phenyl, a 5-or 6-membered cycloalkyl or a 5-or 6-membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from : -C1-3alkyl, -C1-3alkoxy, -C1-3alkylOH, halogen, -CN, -CF3, -NH2,-CO2H and -OH; or (iii) a second ring Rf, which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 5-or 6-membered cycloalkyl group or a 5-or 6-membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from:-C1 3alkyl, -C1-3alkoxy, -C1-3alkylOH, halogen, -CN, -CF3, -NH2,-CO2H and-OH; and pharmaceutical acceptable derivatives thereof.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 530004 530 WO 02/100830 PCT/GB02/02721 1 PYRROLIDINE DERIVATIVES AS FACTOR XA INHIBITORS Field of the Invention 5 The present invention relates to a novel class of chemical compounds, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly use in the amelioration of a clinical condition for which a Factor Xa inhibitor is indicated. 10 Background of the Invention Factor Xa is a member of the trypsin-like serine protease class of enzymes. It is a key enzyme in the coagulation cascade. A one-to-one binding of Factors Xa and Va with calcium ions and phospholipid converts prothrombin into thrombin. Thrombin plays a central role in 15 the mechanism of blood coagulation by converting the soluble plasma protein, fibrinogen, into insoluble fibrin. The insoluble fibrin matrix is required for the stabilisation of the primary hemostatic plug. Many significant disease states are related to abnormal hemostasis. With respect to the coronary arterial vasculature, abnormal thrombus formation due to the rupture of an established atherosclerotic plaque is the major cause of acute myocardial infarction 20 and unstable angina. Both treatment of an occlusive coronary thrombus by thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA) are often accompanied by an acute thrombotic reclosure of the affected vessel which requires immediate resolution. With respect to the venous vasculature, a high percentage of patients undergoing major surgery in the lower extremities or the abdominal area suffer from thrombus formation in the 25 venous vasculature which can result in reduced blood flow to the affected extremity and a pre-disposition to pulmonary embolism. Disseminated intravascular coagulopathy commonly occurs within both vascular systems during septic shock, certain viral infections and cancer and is characterised by the rapid consumption of coagulation factors and systemic coagulation which results in the formation of life-threatening thrombi occurring throughout 30 the vasculature leading to widespread organ failure. Beyond its direct role in the formation of fibrin rich blood clots, thrombin has been reported to have profound bioregulatory effects on a number of cellular components within the vasculature and blood, (Shuman, M.A., Ann. NY Acad. Sci., 405: 349 (1986)). 35 A Factor Xa inhibitor may be useful in the treatment of acute vascular diseases such as coronary thrombosis (for example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty, transient ischemic attacks, pulmonary 40 embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal WO 02/100830 PCT/GB02/02721 2 narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke. They may also have utility as anti-coagulant agents both in-vivo and ex-vivo, and in oedema and inflammation. Thrombin has been reported to contribute to lung fibroblast proliferation, thus, Factor Xa inhibitors could be useful for the treatment of some 5 pulmonary fibrotic diseases. Factor Xa inhibitors could also be useful in the treatment of tumour metastasis, preventing the fibrin deposition and metastasis caused by the inappropriate activation of Factor Xa by cysteine proteinases produced by certain tumour cells. Thrombin can induce neurite retraction and thus Factor Xa inhibitors may have potential in neurogenerative diseases such as Parkinson's and Alzheimer's disease. They 10 have also been reported for use in conjunction with thrombolytic agents, thus permitting the use of a lower dose of thrombolytic agent. The present invention provides novel Factor Xa inhibitors. Compounds of the present invention have oral bioavailability and PK profiles suitable for acute and chronic therapies. 15 Summary of the Invention The present invention provides compounds of formula (I): R\ / 20 wherein: R1 represents hydrogen, -C^alkyl, -C3^alkenyl, -C2.3alkylNRbRc, -C2^alkyiNHCORb, phenyl or a 5- or 6- membered aromatic heterocyclic group, the phenyl or 5- or 6- membered aromatic heterocyclic group being optionally substituted by halogen, or R1 represents a 25 group X-W, wherein X represents -C^alkylene- and W represents -CN, -C02H, -CONRbRc, -COC^alkyl, -COaC^alkyl, phenyl or 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one or more substitutents WO 02/100830 PCT/GB02/02721 3 selected from: -C^alkyl, -C^alkoxy, -C^alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; R2 and R3 independently represent hydrogen, -ChalkyI or -CF3 with the proviso that one of 5 R2 and R3 is -C^alkyi or -CF3 and the other is hydrogen; Rb and Rc independently represent hydrogen or -C^alkyl; A represents a group selected from: 10 =VCN a n -(C2 3)alkenylene N- CO N-N Z represents one or two optional substituents independently selected from halogen and OH, W represents an optional substituent -C^alkyl, alk represents C2.3alkylene or C^alkenylene, 15 T represents a heteroatom selected from O, S or N; B represents one or more optional substituents on ring carbon atoms selected from: (i) one or more substituents selected from -CF3, -F, -C02H, -C^alkyl, -C^alkylOH, -(Ci_ 3alkyl)NRbRc, -(C0^alkyl)CONRbRc and -(C0^alkyl)CO2C^alkyl, -CONHC2.3alkylOH, -20 CH2NHC2_3alkylOH, -CHjOC-^alkyl and -CH2S02C^alkyl; (ii) a group -Y-R®, Y represents -C^alkylene-, -CO-, -Ci^alkylNH-, -C^alkylNHCO-, -C^alkylNHSOa-, -CH2NHS02CH2- or a direct link, R9 represents phenyl, a 5- or 6- membered cycloalkyl or a 5- or 6- membered heterocycle 25 containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -Chalky!, -C^alkoxy, -C^alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; or 4 (iii) a second ring R{ which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 5- or 6- membered cycloalkyl group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: -Chalky!, -C^alkoxy, -C-,_ 5 3alkylOH, halogen, -CN, -CF3) -NH2, -C02H and -OH; and pharmaceutical^ acceptable derivatives thereof. Further aspects of the invention are: A pharmaceutical composition comprising a compound of the invention together 10 with a pharmaceutical carrier and/or excipient. A compound of the invention for use in therapy. Use of a compound of the invention for the manufacture of a medicament for the treatment of a patient suffering from a condition susceptible to amelioration by a Factor Xa Also described herein is a method of treating a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor comprising administering a therapeutically effective amount of a compound of the invention. R1 represents hydrogen, -Ci.6alkyl, -C2-6alkenyl or a group X-W, wherein X represents -C]. 3alkylene- and W represents -CN, -C02H, -CONRbR°, -COCi-6alkyl, -C02C1.6alkyl, phenyl or 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one inhibitor. Detailed Description of the Invention The present invention also provides compounds of formula (la): (la) wherein: intellectual Property Oifics of M.2. 2 3 JUU 20Q5 WO 02/100830 PCT/GB02/02721 5 or more substitutents selected from: -C^alkyl, -C1.3alkoxy, -C^alkylOH, halogen, -CN, -CF3, -NHZ, -C02H and -OH; R2 and R3 independently represent hydrogen, -Chalky! or -CF3 with the proviso that when 5 one of R2 and R3 is -Chalky! or -CF3, the other is hydrogen; Rb and Rc independently represent hydrogen or -Ci_3alkyl; A represents a group selected from: 10 Z represents an optional substituent halogen, alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; B represents one or more optional substituents on ring carbon atoms selected from: (i) one 15 or more substituents selected from -CF3, -F, =0, -C02H, -Ci.6alkyl, -C^alkylOH, -(Cv 3alkyl)NRbRc, -(Co-3alkyl)CONRbRc and -(C0Jalkyl)CO2C1 ^alkyl; (ii) a group -Y-Re, Y represents -C^alkylene-, -CO-, -C^alkylNH-, -C1.3alkylNHCO-, -C1.3alkylNHS02-, -CH2NHS02CH2- or a direct link, 20 Re represents phenyl, a 5- or 6- membered cycioaikyi or a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -C^alkyl, -C^alkoxy, -C^alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; or (iii) a second ring Rf which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 25 5- or 6- membered cycloalkyi group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: -Chalky!, -C^alkoxy, -C-). 3alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; and pharmaceutical^ acceptable salts of solvates thereof. 30 WO 02/100830 PCT/ GB02/02721 6 The compounds of formula (1) and (la) contain chiral (asymmetric) centres. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present invention. 5 When R1 represents a group X-W: Preferably, X represents -C^alkylene-, more preferably -methylene-. Preferably, W represents -CN, -C02H, -CONRbRc, -COC-i^alkyl, -C02Ci^alkyl or a 5- or 6-membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. Preferably, R1 represents hydrogen, -Chalky!, -C2-ealkenyl or a group X-W wherein 10 X represents -C^alkylene- and W represents -CN, -C02H, -CONRbRc, -COC^alkyl, -C02C-i^alkyl or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. More preferably, R1 represents a group selected from hydrogen, -CH2CN, -CH2CONH2, -CH2COC1.6alkyl and -CH2C02Ci.ealkyl. 15 In another prefered aspect, R1 represents hydrogen, -C^alkyl, -C^alkenyl, -C2.3alkylNRbRc, -C2.3alkylNHCORb, phenyl or a 5- or 6- membered aromatic heterocycle, or R1 represents a group X-W wherein X represents -Ci„3alkylene- and W represents -CN, -C02H, -CONRbR°, -COCi.6alkyl, -C02Ci„6alkyl, or a 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. More preferably, R1 20 represents hydrogen, -C^aikyl, -C3^alkenyl, -C2^alkylNRbRc, -C2^alkylNHCORb, or R1 represents a group X-W wherein X represents -Ci_3alkylene- and W represents -CN, -C02H, -CONRbRc, -COC^alkyl, -C02Ci^alkyl, or a 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S. Even more preferably, R1 represents a group selected from: hydrogen, -C^alkyl, -CH2CH=CH2, -25 CH2CH2N(CH3)2, -CH2CH2NHCOCH3, -CH2CN, -CH2C02H, -CH2C02CH3, -CH2C02t-Butyl, -CH2CONH2, -CH2COCH2CH3i -CH2COt-Butyl, -CH2C02CH2CH3, WO 02/100830 PCT/GB02/02721 7 Preferably, R2 represents -C^alkyl or hydrogen, more preferably methyl or hydrogen. Preferably, R3 represents -Chalky! or hydrogen, more preferably methyl or hydrogen. 5 Preferably B represents hydrogen or a substituent selected from -Chalky!, -(Ci_ 3alkyl)NRbRc, -(CMalkyl)CONRbRc, -CONHC^alkylOH, -CH2NHC2.3alkylOH, -CH2OC^alkyl and -CH2S02Ci_3alkyl or a group -Y-R6 where Y represents -CO- or -CH2- and R® represents a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N, S. Preferably, the substitution is in the 2-position relative to the oxygen atom in 10 the morpholine ring. More preferably, B represents hydrogen or a substituent selected from -C^alkyl, -CONHCHa, -CONHCH2CH(OH)CH3, -CH2NH(CH3)2, -CH2OCH3, -CH2S02CH3, -CH2NHCH2CH(OH)CH3, Even more preferably, B represents hydrogen or methyl. Most preferably B represents 15 hydrogen. Preferably 2 represents halogen. More preferably, Z represents chlorine. Preferably, A represents a substituent selected from: 20 Me Br WO 02/100830 PCT/GB02/02721 8 More preferably, A represents a substituent selected from: * -"-OCX ■% ,s- ci CI Even more preferably, A represent a substituent selected from: ~ccx Most preferably, A represents (chlorothienyl)ethene. 10 In another preferred aspect of the invention, A represents chloronaphthylene, chiorobenzothiophene, chlorobithiophene or chlorophenyiethene. More preferably, A represents a group selected from: 6-chloronaphthyl, 5'-chloro-2,2'-biothiophene, (4-chlorophenyl)ethene, 6-chloro-1 -benzothiophene. 15 It is to be understood that the present invention covers all combinations of preferred groups described hereinabove. Hence, in a preferred aspect the present invention provides compounds of formula (la) wherein: 20 R1 represents hydrogen, -Chalky!, -C3^alkenyl, -C2^alkylNRbRc, -C2^alkylNHCORb, phenyl or a 5- or 6- membered aromatic heterocycle, or a group X-W wherein X represents -Ci. 3alkylene- and W represents -CN, -C02H, -CONRbRc, -COCi.6alkyi, -CC^C^alkyl, or a 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S; WO 02/100830 PCT/GB02/02721 9 R2 and R3 independently represent hydrogen or -Chalky! with the proviso that one of R2 and R3 is -C^alkyl and the other is hydrogen; Rb and Rc independently represent hydrogen or -Chalky!; B represents hydrogen or a substituent selected from -C^alkyl, -(C1_3alkyl)NRbRc, -(C0. 5 3alkyl)CONRbR°, -CONHC^alkylOH, -CH2NHC2.3alkylOH, -CHzOC^alkyl and -CH2S02C^. 3alkyl or a group -Y-R® where Y represents -CO- or -CH2- and Re represents a 5- or 6-membered heterocycle containing at least one heteroatom selected from O, N, S. A represents: and pharmaceutical^ acceptable derivatives thereof. In a more preferred aspect the present invention provides compounds of formula (la) wherein: 15 R1 represents hydrogen, -C^alkyl, -C3.6alkenyl, -C2.3alkylNRbRc, -C2.3alkylNHCORb, or a group X-W wherein X represents -C^alkylene- and W represents -CN, -C02H, -CONRbRc, -COC^alkyl, -C02C1^alkyl, or a 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S; R2 and R3 independently represent hydrogen or -Chalky! with the proviso that one of R2 and 20 R3 is -C-i^alkyl and the other is hydrogen; B represents hydrogen or a substituent selected from -C^alkyl, -CONHCH3, -CONHCH2CH(OH)CH3, -CH2NH(CH3)2i -CH2OCH3i -CH2S02CH3i -CH2NHCH2CH(OH)CH3, Me Br 10 WO 02/100830 PCT/GB02/02721 A represents a group selected from: and pharmaceutical^ acceptable derivatives thereof. As used herein, the terms "alkyl" and "alkoxy" mean both straight and branched chain 10 saturated hydrocarbon groups. Examples of alkyl groups include methyl (-CH3), ethyl (-C2H5), propyl (-C3H7) and butyl (-C4Hg). Examples of alkoxy groups include methoxy (-OCH3) and ethoxy (-OC2H5). As used herein, the term "alkylene" means both straight and branched chain saturated 15 hydrocarbon linker groups. Examples of alkylene groups include methylene (-CH2-) and ethylene (-CH2CH2-). As used herein, the term "alkenyl" means both straight and branched chain unsaturated hydrocarbon groups, wherein the unsaturation is present only as double bonds. Examples of 20 aikenyi groups include ethenyi (-CH=CH2) and propenyl (-CH=CHCH3 or-CH2CH=CH2). As used herein, the term "alkenylene" means both straight and branched chain unsaturated hydrocarbon linker groups, wherein the unsaturation is present only as double bonds. Examples of alkenylene groups includes ethenylene (-CH=CH-) and propenylene (-CH2-25 CH=CH- or-CH=CH-CH2-). As used herein, the term "alkynyl" means both straight and branched chain unsaturated hydrocarbon groups, wherein the unsaturation is present only as triple bonds. Examples of alkynyl groups include propynyl (e.g. -CH2-CsCH). 30 As used herein, the term "halogen" means fluorine, chlorine, bromine and iodine. WO 02/100830 PCT/GB02/02721 11 As used herein, the term "cycloalkyi group" means an aliphatic ring (saturated carbocyclic ring). Examples of cycloalkyi groups include cyclopentyl and cyclohexyl. 5 As used herein, the term "heterocyclic group" means a ring containing one or more heteroatoms selected from: nitrogen, sulphur and oxygen atoms. The heterocycle may be aromatic or non-aromatic, i.e., may be saturated, partially or fully unsaturated. Examples of 5-membered groups include thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl and furanyl, 6-membered 10 groups include pyridyl, pyrazyl and pyrimidyl, morpholinyl, thiomorpholinyl, 7- membered groups include azepinyl. As used herein, the term "pharmaceuticaliy acceptable" means a compound which is suitable for pharmaceutical use. 15 As used herein, the term "pharmaceuticaliy acceptable derivative", means any pharmaceuticaliy acceptable salt, solvate, or prodrug e.g. ester or carbamate, or salt or solvate of such a prodrug, of a compound of formula (I) or (la), which upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (i) or (la), 20 or an active metabolite or residue thereof. Preferred pharmaceuticaliy acceptable derivatives are salts and solvates. Suitable salts according to the invention include those formed with both organic and inorganic acids and bases. Pharmaceuticaliy acceptable acid addition salts include those 25 formed from mineral acids such as: hydrochloric, hydrobromic, sulphuric, phosphoric, acid; and organic acids such as: citric, tartaric, lactic, pyruvic, acetic, trifiuoroacetic, succinic, oxalic, formic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids. Pharmaceuticaliy acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, 30 alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine. Particularly preferred pharmaceuticaliy acceptable salts include those formed from hydrochloric, trifiuoroacetic and formic acids. 35 Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compound of formula (I) or (la) 40 are within the scope of the invention. WO 02/100830 PCT/GB02/02721 12 Salts and solvates of compounds of formula (I) or (la) which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceuticaliy acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or 5 associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) or (la) and their pharmaceuticaliy acceptable salts and solvates. As used herein, the term "prodrug" means a compound which is converted within the body, 10 e.g. by hydrolysis in the blood, into its active form that has medical effects. Pharmaceuticaliy acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. Esters may be active in 15 their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceuticaliy acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Preferred compounds of the invention include: 20 6-Chloro-N-{(3S)-1 -[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-2-(2,6-dimethylmorpholin-4-yl)-1 -methyl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(3-methylmorpholin-4-yl)-2-oxoethyr|-2-oxopyrrolidin-3-25 yl}naphthalene-2-sulfonamide, 6-Chloro-N-((3S)-1 -{(1 S)-1 -methyl-2-oxo-2-[3-(pyrrolidin-1 -ylcarbonyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 6-Chloro-N-[(3S)-1-((1S)-1-methyl-2-{2-[(methylsulfonyl)methyl]morpholin-4-yl}-2-oxoethyl)-2-oxopyrroiidin-3-yijnaphthalene-2-sulfonamide, 30 6-Chloro-N-((3S)-1 -{(1 S)-2-[2-(methoxymethyl)morpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-methylmorpholine-2-carboxamide, 6-Chloro-N-((3S)-1 -{(1 S)-1 -methyI-2-oxo-2-[2-(pyrrolidin-1 -ylcarbonyl)morpholin-4-yl]ethyl}-35 2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N,N-dimethylmorpholine-2-carboxamide, 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyi)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-(2-hydroxypropyl)morpholine-2-carboxamide, WO 02/100830 PCT/GB02/02721 13 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrroiidin-1-yl)propanoyl]-N,N-diisopropylmorpholine-2-carboxamide, 6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(piperidin-1-yIcarbonyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 5 6-Chloro-N-[(3S)-1 -((1 S)-1 -methyl-2-{2-[(methylamino)methyl]morpholin-4-yi}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphtbalene-2-sulfonamide formate, 6-Chloro-N-((3S)-1-{(1 S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 S)-2-(2-{[(2-hydroxypropyl)amino]methyl}morpholin-4-yl)-1 -methyl-2-10 oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide formate, 6-Chioro-N-[(3S)-1-((1S)-2-{2-[(dimethylamino)methyl]morpholin-4-yl}-1-methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide formate, 6-Chloro-N-[(3S)-1 -((1 S)-2-{2-[(diisopropylamino)methyl]morpholin-4-yl}-1 -methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide formate, 15 6-Chioro-N-((3S)-1 -{(1 S)-1 -methyl-2-oxo-2-[2-(piperidin-1 -ylmethyl)morpholin-4-y!]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide formate, 6-Chloro-N-((3S)-1 -{(1 S)-2-[(2R,6S)-2,6~dimethylmorpholin-4-yl]-1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 6-Chloro-N-{(3R)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyI]-2-oxopyrrolidin-3-20 yl}naphthalene-2-sulfonamide, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yi}-2,2'-bithiophene-5-sulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 25 N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-t(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N2-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 5i-Chioro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-30 oxopyrrolidin-3-yl}-2,2,-bithiophene-5-sulfonamide, Methyl N-[(5'-chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2'-bithiophene-5-sulfonamide, 35 N-[(5,-Chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 :methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, (E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-40 oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide, WO 02/100830 PCT/GB02/02721 14 Methyl N-{t(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-y|-2-oxoethyl]-2-oxopyrroiidin-3-yl}glycinate, N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, 5 6-Chloro-N-(3-furylmethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyI]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-ethyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-10 yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide, N-2-[(6-Chloro-2-naphthyl)sulfonyI]-N-2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 15 6-Chloro-N-(2-furylmethyl)-N-{(3S)-1 -[(1 S)-1-methyl-2-rnorpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl>naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-20 1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamide formate, 25 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 R)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chioro-'N-meihyi-N-{(3S)-1 -[(1 R)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-30 yl}naphthalene-2-sulfonamide, 6-Chloro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methy!-2-morpholin-4-yl-2-oxoethyI]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalerie-2-sulfonamide, 35 6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morphoIin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N1-methyl-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N-Allyl-6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-40 yl}naphthalene-2-sulfonamide, WO 02/100830 PCT/GB02/02721 15 Methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, Ethyl N-[(6-chloro-2-naphthyl)sulfonyQ-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5 terf-Butyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, 6-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-10 yl}naphthalene-2-sulfonamide, 5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yI-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzofuran-2-sulfonamide, (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethylJ-2-oxopyrrolidin-3-yl}ethenesulfonamide, 15 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 -benzothiophene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 -benzothiophene-2-sulfonamide, 5-Chloro-3-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-20 yl}-1 -benzothiophene-2-sulfonamide, 3-Cyano-N-{(3S)-1 -[(1 S)-1 -methyI-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide, 4-Cyano-N-{(3S)-1-[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}benzenesulfonamide, 25 5-(5-Chloro-1,3,4-thiadiazol-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholiri-4-yl-2-oxoethyl]-2-oxopyrrolidiri-3-yl}thiopherie-2-sulfonamide, 5-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}thieno[2,3-b]pyridine-2-sulfonamide, 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-30 yl}thieno[3,2-b]pyridine-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide, N2-[(6-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 35 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide, N2-[(5-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-40 phenylnaphthalene-2-sulfonamide, WO 02/100830 PCT/GB02/02721 16 6-Chloro-N-(4-fluorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-4-ylnaphthalene-2-suifonamide, 5 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-3-ylnaphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-thien-3-ylnaphthalene-2-su!fonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-10 1-methyl-2-oxoethyI}-2-oxopyrrolidin-3-yl)glycinamideI (E)-2-(3-Chloro-4-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}etheriesulfonamide, (E)-2-(4-Chioro-3-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yi-2-oxoethyi]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 15 6-Chioro-N-{(3S)-1-[(1 S)-1-methyi-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrroiidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-ylethyI)naphthalene-2-sulfonamide formate, 6-Chioro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-20 2-oxopyrrolidin-3-y!}naphthalene-2-sulfonamide formate, N-t2-([(6-Chloro-2-naphthyI)sulfonyl]{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide, 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyI-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 H-indole-2-sulfonamide, 25 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyi-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1,3-benzothiazole-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methy!-2-(2-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, (E)-2-(5-Chiorothien-2-yi)-N-methyi-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-30 oxopyrrolidin-3-yl}ethenesulfonamide, and (E)-2-(5-Chlorothien-2-yl)-N-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide. More preferred compounds of the invention include: 35 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chioro-N-{(3S)-1-[(1 S)-2-(2)6-dimethylmorpholin-4-yl)-1-methyl-2-oxoethyi]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chioro-N-{(3S)-1 -[(1 S)-1 -methyl-2-(3-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-40 yl}naphthalene-2-sulfonamide, WO 02/100830 PCT/GB02/02721 17 6-Chloro-N-[(3S)-1 -((1 S)-1 -methy!-2-{2-[(methylsulfonyl)methyl]morpholin-4-yl}-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sulfonamide, 6-Chloro-N-((3S)-1 -{(1 S)-2-[2-(methoxymethyl)morpholin-4-yl]-1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 5 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyi)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-methylmorpholine-2-carboxamide, 4-[(2S)-2-((3S)-3-{[(6-Chloro-2-naphthyl)sulfonyI]amino}-2-oxopyrrolidin-1-yl)propanoyl]-N-(2-hydroxypropyl)morpholirie-2-carboxamide, 6-Chloro-N-((3S)-1-{(1S)-1-methyl-2-oxo-2-[2-(pyrrolidin-1-ylmethyl)morpholin-4-yl]ethyl}-2-10 oxopyrrolidin-3-yl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 S)-2-(2-{[(2-hydroxypropyl)amino]methyl}morpholin-4-yl)-1 -methyI-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide formate, 6-Chloro-N-[(3S)-1 -((1 S)-2-{2-[(dimethylamino)methyl]morpholin-4-yl}-1 -methyl-2-oxoethyl)-2-oxopyrrolidin-3-yl]naphthalene-2-sutfonamide formate, 15 6-Chloro-N-((3S)-1 -{(1 S)-1 -methyl-2-oxo-2-[2-(piperidin-1 -ylmethyl)morpholin-4-yl]ethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide formate, 6-Chloro-N-((3S)-1 -{(1 S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)naphthalene-2-sulfonamide, 6-Chloro-N-{(3R)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-20 yl}naphthalene-2-sulfonamide, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2'-bithiophene-5-sulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 25 N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methy!-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N2-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 5"-Chioro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyI-2-morpholin-4-yl-2-oxoethyl]-2-30 oxopyrrolidin-3-yl}-2,2'-bithiophene-5-sulfonamide, Methyl N-[(5'-chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5'-Chloro-N-{(3S)-1 -[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2'-bithiophene-5-sulfonamide, 35 N-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, (E)-2-(4-ChJorophenyl)-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-40 oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide, WO 02/100830 PCT/GB02/02721 18 Methyl N-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, N-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, 5 6-Chioro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-ethyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyi]-2-oxopyrrolidin-3-10 yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide, N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 15 6-Chloro-N-(2-furylmethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyl)naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-20 1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamide formate, 25 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 R)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-methyl-N-{(3S)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrro!idin-3-30 yl}naphthalene-2-sulfonamide, 6-Chloro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 35 6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N 1 -methyl-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N-Allyl-6-chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-40 yl}naphthalene-2-sulfonamide, WO 02/100830 PCT/GB02/02721 19 Methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, Ethyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5 fe/f-Butyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 s)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, 6-Chloro-N-{(3R)-1-[(1R)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-10 yl}naphthalene-2-sulfonamide, (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 -benzothiophene-2-sulfonamide, 15 6-Chioro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 -benzothiophene-2-sutfonamide, 5-Chloro-3-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1-benzothiophene-2-sulfonamide, 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-20 yl}thieno[3,2-b]pyridine-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide, N2-[(6-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 25 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulfonamide, N2-[(5-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-30 phenylnaphthalene-2-sulfonamide, 6-Chloro-N-(4-fluorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-pyridin-4-ylnaphthalene-2-sulfonamide, 35 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl)-N-pyridin-3-ylnaphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-thien-3-ylnaphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-40 1 -methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)g)ycinamide, WO 02/100830 PCT/GB02/02721 20 (E)-2-(4-Chloro-3-hydroxyphenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2- oxopyrrolidin-3-yl}ethenesulfonamide, 6-Chloro-N-{(3S)-1 -[(1 s)-1 -methyl-2-morpholin-4-yi-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morphoiir>-4-ylethyl)naphthalene-2-sulfonamide formate, 5 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yi}-N-(2-pyrrolidin-1 -ylethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrroiidin-3-yl}naphthalene-2-sulfonamide formate, N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-10 oxopyrrolidin-3-yl}amino)ethyl]acetamide, 5-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-1 H-indole-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(2-methylmorpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, and 15 (E)-2-(5-Chlorothien-2-yl)-N-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide. Even more preferred compounds of the invention include: (E)-2-(4-Chlorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-20 oxopyrrolidin-3-yl}ethenesulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yi-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2'-bithiophene-5-sulfonamide, 25 N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N2-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyi-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 5'-Chioro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-30 oxopyrroiidin-3-yl}-2,2'-bithiophene-5-sulfonamide, Methyl N-[(5'-chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5'-Chioro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2'-bithiophene-5-sulfonamide, 35 N-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 ,[(1 s)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl>glycine, (E)-2-(4-Chiorophenyl)-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-40 oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide, WO 02/100830 PCT/GB02/02721 21 Methyl N-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 6-Chloro-N-(3-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 5 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-ethyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-10 oxobutyl)naphthalene-2-sulfonamide, N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 6-Chloro-N-(2-furylmethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 15 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-thiazol-2-ylmethyi)naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-20 methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamide formate, 25 6-Chloro-N-(cyanomethyl)-N-{(3S)-1 -[(1S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chioro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-30 2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, N-Allyl-6-chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, Methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 35 fert-Butyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycine, (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-40 oxopyrrolidin-3-ylJethenesulfonamide, WO 02/100830 PCT/GB02/02721 22 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrroliclin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-su)fonamide, N2-[(6-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 5 N2-[(6-Chioro-2-naphthyl)sulfonyl]-N2-((3S)-1 -{(1 S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]- 1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulforiamide formate, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2~ 10 pyrrolidin-1 -ylethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]- 2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide formate, and N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyf[acetamide. 15 In another preferred aspect compounds of the invention also include: 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 5'-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2'-20 bithiophene-5-sulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 5'-Chloro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yi-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2,-bithiophene-5-sulfonamide, 25 Methyl N-[(5'-chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yi}glycinate, 5'-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-2,2'-bithiophene-5-sulfonamide, 6-Chioro-N-(3-furyimethyi)-N-{(3S)-1-[(lS)-1-methyi-2-morpholin-4-yl-2-oxoethyl]-2-30 oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-3-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphtha!ene-2-sulfonamide, 35 N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-f(1S)-1-methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-40 thiazol-2-ylmethyl)naphthalene-2-sulfonamide, WO 02/100830 PCT/GB02/02721 23 6-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonatnide, 6-Chioro-N-methyl-N-{(3S)-1 -[(1 S)-1 -methyl-2-morphoiin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 5 N-Allyl-6-chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrroiidin-3-yl}naphthalene-2-sulfonamide, Methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, and N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-10 oxopyrrolidin-3-yl}glyoine. The compounds of formula (I) or (la) are Factor Xa inhibitors and as such are useful in the treatment of clinical conditions susceptible to amelioration by administration of a Factor Xa inhibitor. Such conditions include acute vascular diseases such as coronary thrombosis (for 15 example myocardial infarction and unstable angina), thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, prevention of vessel luminal narrowing (restenosis), and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke; in oedema and PAF 20 mediated inflammatory diseases such as adult respiratory shock syndrome, septic shock and reperfusion damage; the treatment of pulmonary fibrosis; the treatment of tumour metastasis; neurogenerative disease such as Parkinson's and Alzheimer's diseases; viral infection; Kasabach Merritt Syndrome; Haemoiytic uremic syndrome; arthritis; osteoporosis; as anti-coagulants for extracorporeal blood in for example, dialysis, blood filtration, bypass, 25 and blood product storage; and in the coating of invasive devices such as prostheses, artificial valves and catheters in reducing the risk of thrombus formation. Accordingly, one aspect of present invention provides a compound of formula (I) or (la) or a physiologically acceptable salt or solvate thereof for use in medical therapy, particularly for 30 use in the amelioration of a clinical condition in a mammal, including a human, for which a Factor Xa inhibitor is indicated. In another aspect, the invention provides a method for the treatment and/or prophylaxis of a mammal, including a human, suffering from a condition susceptible to amelioration by a 35 Factor Xa inhibitor which method comprises administering to the subject an effective amount of a compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof. In another aspect, the present invention provides the use of a compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof, for the manufacture of a WO 02/100830 PCT/GB02/02721 24 medicament for the treatment and/or prophylaxis of a condition susceptible to amelioration by a Factor Xa inhibitor. Preferably, the condition susceptible to amelioration by a Factor Xa inhibitor is selected from 5 coronary thrombosis (for example myocardial infarction and unstable angina), pulmonary embolism, deep vein thrombosis and the prevention of thromboembolic events associated with atrial fibrillation, e.g. stroke; It will be appreciated that reference to treatment includes acute treatment or prophylaxis as 10 well as the alleviation of established symptoms. While it is possible that, for use in therapy, a compound of the present invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. 15 In a further aspect, the invention provides a pharmaceutical composition comprising at least one compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof in association with a pharmaceuticaliy acceptable carrier and/or excipient. The carrier and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of 20 the formulation and not deletrious to the receipient thereof. Accordingly, the present invention further provides a pharmaceutical formulation comprising at least one compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof, thereof in association with a pharmaceuticaliy acceptable carrier and/or excipient. 25 The carrier and/or excipient must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deletrious to the receipient thereof. In another aspect, the invention provides a pharmaceutical composition comprising, as active ingredient, at least one compound of formula (I) or (la) or a pharmaceuticaliy 30 acceptable salt or solvate thereof in association with a pharmaceuticaliy acceptable carrier and/or excipient for use in therapy, and in particular in the treatment of human or animal subjects suffering from a condition susceptible to amelioration by a Factor Xa inhibitor. There is further provided by the present invention a process of preparing a pharmaceutical 35 composition, which process comprises mixing at least one compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof, together with a pharmaceuticaliy acceptable carrier and/or excipient. WO 02/100830 PCT/GB02/02721 25 The compounds for use according to the present invention may be formulated for oral, buccal, parenteral, topical, rectal or transdermal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or the nose). 5 For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceuticaliy acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. 10 potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions or they may be presented as a dry product for constitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional means with 15 pharmaceuticaliy acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents 20 as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. 25 For buccal administration the compositions may take the form of tablets or lozenges formulated in a conventional manner. The compounds according to the present invention may be formulated for parenteral administration by injection, e.g. by bolus injection or continuous infusion. Formulations for 30 injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, 35 before use. The compounds according to the present invention may be formulated for topical administration by insufflation and inhalation. Examples of types of preparation for topical administration include sprays and aerosols for use in an inhaler or insufflator. WO 02/100830 PCT/GB02/02721 26 Powders for external application may be formed with the aid of any suitable powder base, for example, lactose, talc or starch. Spray compositions may be formulated as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, such as metered dose inhalers, with the use of a suitable propellant. 5 The compounds according to the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. 10 In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds according to the present invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in 15 an acceptable oil) or ion exchange resins or as sparingly soluble derivatives, for example, as a sparingly soluble salt. A proposed dose of the compounds according to the present invention for administration to a human (of approximately 70kg body weight) is 0.1 mg to 1g, preferably to 1mg to 500mg of 20 the active ingredient per unit dose, expressed as the weight of free base. The unit dose may be administered, for example, 1 to 4 times per day. The dose will depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The dosage will also depend on the route of administration. The 25 precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian. The compounds of formula (I) or (la) may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a 30 compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof together with a further therapeutic agent. When a compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof is used in combination with a second therapeutic agent active against the same 35 disease state the dose of each compound may differ from that when the compound is used alone. The compounds of the present invention may be used in combination with other antithrombotic drugs such as thrombin inhibitors, thromboxane receptor antagonists, prostacyclin mimetics, phosphodiesterase inhibitors, fibrinogen antagonists, thrombolytic drugs such as tissue plaminogen activator and streptokinase, non-steroidal anti-40 inflammatory drugs such as aspirin, and the like. WO 02/100830 PCT/GB02/02721 27 The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceuticaliy acceptable carrier or excipient comprise 5 a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either the Factor Xa inhibitor or the second therapeutic 10 agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. 15 When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art. When a compound of formula (I) or (la) or a pharmaceuticaliy acceptable salt or solvate thereof is used in combination with a second therapeutic agent active against the same 20 disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. 25 The compounds of formula (I) or (la) and physiologically acceptable salts or solvates thereof may be prepared by the processes described hereinafter, said processes constituting a further aspect of the invention. In the following description, the groups are as defined above for compounds of formula (i) or (ia) unless otherwise stated. 30 According to a further aspect of the present invention, there is provided a process (A) for preparing a compound of formula (I) or (la), which process comprises reacting a compound of formula (II) with a compound of formula (III). WO 02/100830 PCT/GB02/02721 28 (11) OH O' B (III) Suitably, the reaction may be carried out in the presence of a coupling agent, for example 1-5 [3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride, HOBt (1-hydroxybenzotriazole), a base, e.g. Et3N (triethylamine), and an organic solvent, e.g. DCM (dichloromethane), suitably at room temperature. It will be appreciated by persons skilled in the art that compounds of formula (I) or (la) may 10 be prepared by interconversion, utilising other compounds of formula (I) or (la) which are optionally protected by standard protecting groups, as precursors. For instance, compounds of formula (I) or (la) where B represents -C1.3alkylNH2, may be converted into compounds of formula (I) or (la) possessing alternative substituents on the heterocyclic ring, e.g. -Ci. 3alkylNRbRc, by methods well known in the art (see for example March, J., Advanced 15 Organic Chemistry, John Wiley & Sons). (IV) 20 WO 02/100830 PCT/GB02/02721 29 wherein P1 is a suitable carboxylic acid protecting group, e.g. t-Butyl, by removal of the protecting group under standard conditions. For example, when P1 represents t-Butyl, removal of the protecting group may be effected under acidic conditions, using for example TFA (trifiuoroacetic acid) in a solvent such as DCM. 5 A compound of formula (IV) may be prepared by reacting a compound of formula (V) with a compound of formula (VI) where P1 is as described above: (V) (VI) 10 Suitably, where X is a leaving group such as a halogen atom, e.g. bromine, the reaction is carried out in the presence of a base, e.g. LiHMDS (lithium hexamethyldisilylamide), potassium carbonate or sodium carbonate. Preferably, the reaction is effected in a suitable organic solvent, e.g. THF, DMF, at a temperature from -78°C to +50°C, preferably -78°C to 15 +20°C. Alternatively, where X is hydroxy, the coupling reaction is carried out using standard reagents such as DiAD (diisopropyl azodicarboxyiate) and n-Bu3P (tri n-Butyi p'nospnine) in a solvent such as tetrahydrofuran, suitably at room temperature. 20 A compound of formula (V) may be prepared by reacting a compound of formula (VII) with a compound of formula (VIII): WO 02/100830 PCT/GB02/02721 30 R' F (VII) OP (VIII) wherein T is a reactive group, such as a halide, preferably chloride, and P1 is as described above. The reaction is conveniently carried out in the presence of a base, e.g. pyridine, and 5 in a suitable solvent, e.g. DCM, suitably at room temperature. A compound of formula (VII) may be prepared from a compound of formula (IX) where P1 is as described above and P2 represents a suitable amine protecting group, e.g. Cbz (benzyloxycarbonyl), by removal of the protecting group under standard conditions. For example, the protecting group may be removed by reaction with hydrogen in the presence of a metal catalyst, e.g. palladium/charcoal at atmospheric pressure. Suitably, the reaction is 15 carried out in an alcoholic solvent, e.g. ethanol, suitably at room temperature. A compound of formula (IX) may be prepared from a compound of formula (X) / NHP' 10 (IX) L (X) WO 02/100830 PCT/GB02/02721 31 by cyclisation, wherein P1 and P2 are as described above and L represents a leaving group, e.g. SMeRX. The ring closure may be performed by treatment with Dowex 2x8 400 mesh OH" resin in a suitable solvent, e.g. MeCN (acetonitrile). Alternatively, the ring closure may 5 be performed by treatment with potassium carbonate in a suitable solvent, e.g. MeCN. Generally R will represent alkyl or aralkyl and X will represent halide, especially iodide or sulphate. Alternatively, a compound of formula (IX) may be prepared from a compound of formula 10 (Xb): (Xb) where P1 and P3 are protecting groups, by reaction with LiOH in a suitable solvent e.g. THF followed by reaction with DPPA (diphenylphosphoryl azide), a base e.g. Et3N (triethylamine) 15 in a suitable solvent e.g. DMF, suitably at room temperature to 70°C. A compound of formula (Xb) may be prepared by reacting a compound of formula (Xb-1) with a. compound of formula (Xb-2) O R2^ R3 N3 (Xb-1) (Xb-2) 20 where L1 is a leaving group e.g. bromine, in the presence of a base e.g. Et3N in a suitable e»rvK/ont a n R/IaOM dviwiu ivio^/n, A compound of formula (X) in which L represents SMeRX may be formed from a compound of formula (XI) SMe ^ o p2hn^ o rZ° r3 25 0 WO 02/100830 PCT/GB02/02721 32 by treatment with RX, where P1 and P2 are as described above and RX is a compound (e.g. Mel, benzyl iodide or Me2S04) capable of converting sulphur in the SMe moiety to a sulphonium salt, in a suitable solvent, e.g. propanone or acetonitriie. 5 A compound of formula (XI) may be prepared by reacting a compound of formula (XII) with a compound of formula (XIII): 10 Suitably, the reaction may be carried out in the presence of a coupling agent, for example 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride, HOBt, a base, e.g. E^N, and an organic solvent, e.g. DCM, suitably at room temperature. There is provided a further process (B) for preparing compounds of formula (IV) from 15 compounds of formula (VII). According to process (B), a compound of formula (IV) may be prepared by reductive amination of a compound of formula (VII) with R1aCHO (where R1a is R1 without a CH2 linker directly attached to the N) using a suitable selective reducing agent to produce a compound of formula (XIV), followed by reaction with a compound of formula (VIII) in the presence of a base, e.g. pyridine, and in a solvent, e.g. DCM, suitably at room 20 temperature. SMe (XII) O (Xlll) R\ N—H (XIV) WO 02/100830 PCT/GB02/02721 33 The reductive amination is conveniently carried out by treatment with sodium triacetoxyborohydride in the presence of an acid such as acetic acid, in a solvent such as DCM, suitably at room temperature. 5 Compounds of formulae (III), (VI), (VIII), (Xb-1), (Xb-2), (X), (XI), (XII) and (Xlll) are known compounds and/or can be prepared by processes well known in the art. The various general methods described above may be useful for the introduction of the 10 desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multistage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product. For example, those skilled in the art will appreciate that, with 15 the use of appropriate protecting groups, the coupling to any of groups -R1, -S02A or formula (III) can be the final step in the preparation of a compound of formula (I) or (la). Hence, in another aspect of the invention, the final step in the preparation of a compound of formula (I) or (la) may comprise the coupling to group -R1 by reacting a compound of formula (XV) with a compound of formula (VI): 20 (XV) Suitably, where X is a leaving group such as a halogen atom, e.g. bromine, the reaction is carried out in the presence of a base, e.g. LiHMDS (lithium hexamethyldisilylamide), potassium carbonate or sodium carbonate. Preferably, the reaction is effected in a suitable 25 organic solvent, e.g. THF, DMF, at a temperature from -78°C to +50°C, preferably -78°C to +20°C. 30 In a further aspect of the present invention, the final step in the preparation of a compound of formula (I) or (la) may comprise the coupling to group -S02A by reacting a compound of formula (XVI) with a compound of formula (VIII): WO 02/100830 PCT/GB02/02721 34 The reaction is conveniently carried out in the presence of a base, e.g. pyridine, and in a suitable solvent, e.g. DCM, suitably at room temperature. 5 In a further aspect of the present invention, a compound of formula (I) where R1 is an aryl or heteroaryl group may be prepared from a compound of formula (XV) by reaction with a compound of formula (XVII): 10 R1-C1 (XVII) where C1 is a suitable coupling group e.g. boronate [B(OH)2] under metal catalysis, for example, with a copper salt such as copper(ll) acetate, in the presence of an organic solvent e.g. DCM and a base, e.g. pyridine and optionally in the presence of molecular sieves. 15 In a further.aspect of the present invention, a compound of formula (I) where A is -S02-CH=CH-aryl, S02-CH=CH-heteroaryl, S02-C(CH3)=CH-aryl or S02-C(CH3)=CH-heteroaryl may be prepared from a compound of formula (XVI) where R1 is hydrogen, by reaction with a compound of formula (Xv'iii), or alternatively with a compound of formula (XiX): 20 T1-S02-C(R)=CH2 (XVIII) T1-SOrC(R)-CH2-T2 (XIX) 25 where T1 and T2 are independently reactive groups, such as a halide, preferably chloride, in the presence of a base e.g. N,N-diisopropylethylamine and a suitable solvent e.g. MeCN, suitably at room temperature, to provide a compound of formula (XV) where A is C(R)=CH2, followed by reaction with a compound of formula (XX): 30 . WO 02/100830 PCT/GB02/02721 35 L-Rh (XX) Where Rh is aryl or heteroaryl and L is a leaving group, e.g. bromine, in the presence of a 5 base e.g. N,N-diisopropylethylamine, and a suitable solvent e.g. dioxane and a suitable transition metal catalyst e.g. di(palladium)tris(dibenzylideneacetone) and a suitable ligand e.g. 2-(di-t-butylphosphino)biphenyI under an inert atmosphere e.g. nitrogen, at a temperature 20-100°C preferably 40°C. 10 In a further aspect of the present invention, a compound of formula (I) where A is a biaryl group may be prepared from a compound of formula (XVI) where R1 is hydrogen and the amino group is optionally protected, for example, as a solid supported derivative derived from reductive amination under standard conditions, by reaction with a compound of formula of formula (XXI): 15 20 wherein T is a reactive group, such as a halide, preferably chloride, and M1 is an aryl or heteroaryl group with a suitable coupling group e.g. halogen, preferably bromide or iodide, in the presence of a suitable solvent e.g. DMF and a suitable base, e.g. N,N-diisopropylethylamine, followed by reaction with a compound of fomula (XXII): 25 M2-C2 (XXII) wherein M2 is an aryl or hsteroary! group and C2 is a suitable coupling group e.g. boronate [B(OH)2], in the presence of a metal catalyst e.g. tetrakis(triphenylphosphine)palladium(0), a base e.g. sodium carbonate, a suitable solvent e.g. THF and optionally in the presence of a 30 cosolvent e.g. H20, followed by removal of any protecting groups under standard conditions, e.g. under standard conditions. Those skilled in the art will appreciate that in the preparation of the compound of formula (I) 35 or (la) or a solvate thereof it may be necessary and/or desirable to protect one or more sensitive groups in the molecule to prevent undesirable side reactions. Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic WO 02/100830 PCT/GB02/02721 36 synthesis" by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups" by P.J. Kocienski (Georg Thieme Verlag 1994). Examples of suitable amino protecting groups include acyl type protecting groups (e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting groups (e.g. benzyloxycarbonyl (Cbz) and substituted 5 Cbz), aliphatic urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl) and alkyl type protecting groups (e.g. benzyl, trityl, chlorotrityl). Examples of suitable oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert-butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as 10 acetate. Various intermediate compounds used in the above-mentioned process, including but not limited to certain compounds of formulae formulae (II), (IV), (V), (VII), (IX), (XIV), (XV) and (XVI) are novel and accordingly constitute a further aspect of the present invention. 15 The present invention will now be further illustrated by the accompanying examples which should not be construed as limiting the scope of the invention in any way. Examples 20 Abbreviations Boc f-Butyloxycarbonyl Cbz Benzyloxycarbonyl THF Tetrahydrofuran 25 DCM Dichloromethane DMF N,N-Dimethylformamide HOBT. 1-Hydroxybenzotriazole br broad m muitipiet 30 q quartet s singlet t triplet d doublet 35 Intermediate 1 fetf-Butvl N-Rbenzvloxvlcarbonvll-L-methionvl-L-alaninate Z-Protected L-methionine (10g) was dissolved in DMF (200ml) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (8.13g) was added followed by HOBT (5.72g) and triethylamine (19.7ml). The mixture was stirred for 1h then L-alanine tert-40 bulyl ester (7.7g) was added and stirring continued for 18h. The mixture was concentrated WO 02/100830 PCT/GB02/02721 37 under reduced pressure and partitioned between diethyl ether and water. The separated organic phase was washed with hydrochloric acid (1M), saturated sodium bicarbonate solution and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (11.9g) as an orange oil which crystallised on standing. 5 Mass spectrum: Found: MH+ 411 Intermediate 2 terf-Butvl N-r(benzvloxv)carbonvH-D-methionvl-L-alaninate Using Z-protected D-methionine, L-alanine ferf-butyl ester, and the procedure described for 10 Intermediate 1, the title compound was prepared. Mass spectrum: Found: MH+ 411 Intermediate 3 te/f-Butvl N-F(benzvloxv)carbonvn-D-methionvl-D-alaninate 15 Using Z-protected D-methionine, D-alanine ferf-butyl ester and the procedure described for Intermediate 1, the title compound was prepared. Mass spectrum: Found: MH+ 411 Intermediate 4 20 ferf-Butvl N-fCbenzvloxvlcarbonvll-L-methionvl-D-alaninate Using Z-protected L-methionine, D-alanine tert-butyl ester and the procedure described for Intermediate 1, the title compound was prepared. Mass spectrum: Found: MH+ 411 25 Intermediate 5 terf-Butvl (2SV2-((3S)-3-fr(benzvloxy)carbonvnaminoV2-oxopvrrolidin-1-vDpropanoate A solution of Intermediate 1 (11.9g) in acetone (75ml) was treated with methyl iodide (18ml) and stirred at room temperature for 72h. The reaction mixture was then concentrated under reduced pressure to give an orange solid that was dissolved in acetonitrile (200ml). Dowex 30 (OH" form) resin (19.42g) was added and the mixture stirred for 18h at room temperature. The mixture was filtered and the resin washed with ethyl acetate. The filtrate was concentrated under reduced pressure to afford a yellow oil which was purified by Biotage™ chromatography (eluting with cyclohexane:ethyl acetate 3:2) to give the title compound (2.92g) as a colourless oil. 35 Mass spectrum: Found: MH+ 363 Intermediate 6 tert-Butyl (2S)-2-((3R)-3-fr(benzvloxy)carbonvnamino)-2-oxopvrrolidin-1-vnpropanoate Using Intermediate 2 and the procedure described for Intermediate 5, the title compound 40 was prepared. WO 02/100830 PCT/GB02/02721 38 Mass spectrum: Found: MH+ 363 Intermediate 7 ferf-Butvl (2RV-2-((3R)-3-{r(benzvloxv^carbonvllamino)-2-oxoDvrrolidin-1-v0proDanoate 5 Using Intermediate 3 and the procedure described for Intermediate 5, the title compound was prepared. Mass spectrum: Found: MH+ 363 Intermediate 8 10 fe/f-Butvl (2R)-2-f(3S)-3-(r(benzvloxv)carbonvnaminoy-2-oxopvrrolidin-1 -vDpropanoate Using Intermediate 4 and the procedure described for Intermediate 5, the title compound was prepared. Mass spectrum: Found: MH+ 363 15 Intermediate 9 feri-Butvl (2SV2-r(3SV3-amino-2-oxopvrrolidin-1 -vllpropanoate A mixture of tert- butyl (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (2.82g), 10% palladium on carbon (0.3g) and ethanol (150ml) was stirred under an atmosphere of hydrogen for 18h. The reaction mixture was filtered through 20 Harbolite™ and the filtrate was concentrated under reduced pressure to give the title compound (1.8g) as a pale yellow oil. 1H NMR (D4MeOH): 8 4.56(1 H, q), 3.57(1 H, dd), 3.49-3.35(2H, 2 x m), 2.48-2.39(1 H, m), 1.88-1.77(1 H, m), 1.47(9H, s), 1.40 (3H, d) ppm. 25 Intermediate 10 ferf-Butvl (2S)-2-f(3RV3-amino-2-oxopvrrolidin-1 -vllpropanoate Using Intermediate 6 and the procedure described for Intermediate 9, the title compound was prepared. *'H NMR (D4MeOH): 6. 4.60(1 H, q), 3.58(11-1, dd), 3.46(1H, dt), 3.41-3.33(1H, m), 2.48-30 2.40(1 H, m), 1.82-1.70(1 H, m), 1.45(9H, s), 1.40(3H, d) ppm. Intermediate 11 ferf-Butvl (2R)-2-lY3RV-3-amino-2-oxopvrrolidin-1 -vllpropanoate Using Intermediate 7 and the procedure described for Intermediate 9, the title compound 35 was prepared. 1H NMR (D4MeOH): 8 4.58(1H, q), 3.75(1H, dd), 3.55-3.41(2H, 2 x m), 2.50(1H, m), 1.90(1H, m), 1.49(9H, s), 1.42(3H, d) ppm. Intermediate 12 40 fe/f-Butvl (2R)-2-IY3S)-3-amino-2-oxopyrrolidin-1 -vllpropanoate WO 02/100830 PCT/GB02/02721 39 Using Intermediate 8 and the procedure described for Intermediate 9, the title compound was prepared. 1H NMR (D4MeOH): 5 4.68(1 H, q), 3.78(1 H, t), 3.56-3.40(2H, 2 x m), 2.52(1 H, m), 1.89(1H, m), 1.48(9H, s), 1.42(3H,d) ppm. 5 Intermediate 13 (2SV2-f(3SV3-f[('Benzvloxv')carbonvllamino)-2-oxopvrrolidin-1 -vl) propanoic acid ferf-Butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.5g) was dissolved in DCM (7ml), and trifiuoroacetic acid (4.7ml) was added. The mixture was 10 stirred at room temperature for 4h and then concentrated under reduced pressure to give the title compound (0.423g) as a colourless oil, which after azeotroping with toluene, crystallised. Mass spectrum: Found: MH+ 307 15 Intermediate 14 fert-Butvl (2S)-2-((3S)-3-fr(6-chloro-2-naphthv0sulfonvl1amino)-2-oxopvrrolidin-1- vlbropanoate A solution of terf-butyl (2S)-2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate (1.8g) in DCM (75ml) was treated with 6-chloronaphthylsulphonyl chloride1 (2.28g) and pyridine (0.705ml) 20 and stirred at room temperature for 72h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was purified by Biotage™ chromatography (eluting with cyclohexane:ethyl acetate 3:1) to give the title compound (2.31 g), as a white solid. Mass spectrum: Found: MH+ 453 25 Intermediate 15 tert- Butyl (2S)-2-((3R)-3-fr(6-chloro-2-naphthvl)sulfonvnamino}-2-oxopvrrolidin-1- vlbropanoate Using intermediate 10 and the procedure descnbed for Intermediate 14, the title compound 30 was prepared. 1H NMR (CDCIg): 6 8.45(1 H, br.s), 7.96-7.83(4H, m), 7.56 (1H, dd), 5.41 (1H, br.s), 4.66 (1H, q), 3.73(1 H, dt), 3.42-3.34(2H, m), 2.62(1 H, m), 2.01 (1H, m), 1.38-1.32(12H, s+d) ppm. Intermediate 16 35 ferf-Butvl (2RV2-((3RV34r(6-chloro-2-naphthvl)sulfonvnarriino>2-oxopvrrolidin-1- vllpropanoate Using Intermediate 11 and the procedure described for Intermediate 14, the title compound was prepared. Mass spectrum: Found: MH+ 453 WO 02/100830 PCT/GB02/02721 40 Intermediate 17 (2S)-2-((3Sy-3-flY6-Chloro-2-naphthv0sulfonvflamino)-2-oxopvrrolidin-1-vlbropanoic acid ferf-Butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1- yl)propanoate (0.643g) was dissolved in DCM (19ml), and trifiuoroacetic acid (19ml) was 5 added. The mixture was stirred at room temperature for 2.5h and then concentrated under reduced pressure. Anhydrous DCM (4ml) was added and the solution concentrated under reduced pressure. Repetitive addition of DCM and concentration under reduced pressure provided the title compound (0.56g) as a white foam. Mass spectrum: Found: MH+ 397 10 Intermediate 18 (2Sy2-f(3R)-3-lf(6-Chloro-2-naphthvDsulfonvnamino)-2-oxopvrrolidin-1-vQpropanoic acid-Using Intermediate 15 and the procedure described for Intermediate 17, the title compound was prepared. 15 Mass spectrum: Found: MH+ 397 Intermediate 19 (2RV2-ff3RV3-(f(6-Chloro-2-naphthvnsulfonvnamino)-2-oxopvrrolidin-1-vl')Dropanoic acid Using Intermediate 16 and the procedure described for Intermediate 17, the title compound 20 was prepared. Mass spectrum: Found: MH+ 397 Intermediate 20 ferf-Butvl (2RV2-(3-azido-2-oxopvrrolidin-1 -vlbropanoate 25 To a solution of D-alanine fert-butylester (1.28g) and N,N-diisopropylethylamine (1.22ml) in acetonitrile (15ml), was added a solution of ethyl 2-azido-4-bromobutanoate (1g) and sodium iodide (0.02g) in acetonitrile (5ml). The mixture was heated at 60'C for 60h and then concentrated under reduced pressure to give a brown oil. This oil was partitioned between DCM and water. The separated organic layer was washed further with water and dried (over 30 magnesium sulphate), and concentrated under reduced pressure. The residual brown oil was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:1) to give the title compound (0.204g) as a mixture of two diastereoisomers. T.l.c. (cyclohexane:ethyl acetate, 2:1) Rf 0.20 35 Intermediates 16 and 21 terf-Butvl (2R)-2-C(3R)-3-!T(6-chloro-2-naphthvl'>sulfonvnamino>-2-oxoDvrrolidin-1- vlbrooanoate (1) terf-Butvl (2R)-2-((3S)-3-ff(6-chloro-2-naphthvl)sulfonvnamino)-2-oxopvrrolidin-1- vlbropanoate (2) WO 02/100830 PCT/GB02/02721 41 A mixture of terf-butyl (2R)-2-(3-azido-2-oxopyrrolidin-1-yl)propanoate (0.204g), 10% palladium on carbon (0.02g) and ethanoi (10ml) was stirred under an atmosphere of hydrogen for 5h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give a yellow oil. The oil (0.150g) in DCM (10ml) 5 was treated with 6-chloronaphthy!sulphonyl chloride1 (0.188g) and pyridine (0.058ml) and stirred at room temperature for 72h. The mixture was washed with water and concentrated under reduced pressure to yield an oil which was purified by Biotage™ chromatography (eluting with cyclohexane:ethyl acetate 2:1) to give the title compounds [(1) - 0.067g and (2) - 0.060g], both as white solids. 10 (1) Mass spectrum: Found: MH+ 453 (2) Mass spectrum: Found: MH+ 453 Intermediate 22 tert-Butvl (2S)-2~f(3S)-3-IT(6-chloro-2-naphthvPsulfonvn(2-oxobLitvDamino1-2-oxopvrrolidin-1-15 vllpropanoate A solution of terf-butyl (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07g) in THF (2ml) was cooled to -78"C under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.186ml), followed by 1-bromo-2-butanone (0.08ml). The resultant solution was allowed to reach room temperature and 20 stirred for a further 72h. Methanol (1ml) was added and the resultant solution concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 10:1, 5:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:5, ethyl acetate and methanol:ethyl acetate 1:9) to give the title compound (0.07g) as a gum. Mass spectrum: Found: MH+ 523 25 Similarly prepared using other commercially available alkyl halides, was: Intermediate 23 fert-Butvl (2S)-2-((3SV3-((2-amino-2-oxoethvn[(6-chloro-2-naphthvnsulfonvllaminoV2- 30 oxopvrrolidin-1 -yHpropanoate Mass spectrum: Found: MH+ 510 Intermediate 24 fert-Butvl (2RV2-f(3S)-3-rf(6-chloro-2-naphthvflsulfonvn(nnethvhamino1-2-oxopvrrolidin-1-35 vllpropanoate The title compound was prepared using Intermediate 21 and methyl tosylate, and the synthetic procedure described for Intermediate 22. Mass spectrum: Found: MH+467 40 Intermediate 25 WO 02/100830 PCT/GB02/02721 42 (2SV2-((3SV3-fH6-Chloro-2-naphthvfisulfonvn(2-oxobutvflaminol-2-oxopvrrolidin-1-vllpropanoic acid ■ tert-Butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyI)amino]-2-oxopyrrolidin-1-yl}propanoate (0.07g) was dissolved in DCM (2ml), and trifiuoroacetic acid (2ml) was added. 5 The mixture was stirred at room temperature for 1.5h and then partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.063g) as an orange gum. Mass spectrum: Found: MH+ 467 10 Intermediate 26 (2SV2-((3S)-3-f(2-Amino-2-oxoethvlW6-chloro-2-naphthvl)sulfonvllaminoy-2-oxopvrrolidin-1-vDpropanoic acid Using Intermediate 23 and similar chemistry to that described for Intermediate 25, the title compound was prepared. 15 Mass spectrum: Found: MH+ 454 Intermediate 27 (2RV2-f(3S)-3-rrf6-Chloro-2-naphthvl)sulfonvn(methvl)amino1-2-oxopyrrolidin-1-vl)propanoic acid 20 Using Intermediate 24 and similar chemistry to that described for Intermediate 25, the title compound was prepared. Mass spectrum: Found: MH+ 411 Intermediate 28 25 (2R)-2-((3S)-3-ir(6-Chloro-2-naphthvDsulfonvHamino'l-2-oxopvrrolidin-1-vDpropanoic acid Using Intermediate 21 and the procedure described for Intermediate 13, the title compound was similarly prepared. Mass spectrum: Found: MH+ 397 30 Intermediate 29 ferf-Butvl (2S)-2"f(3SV3-IT(6-chloro-2-naphthv0sulfonvn(2-furvlmethvnamino,l-2-oxopvrrolidin-1-vllpropanoate A solution of ferf-butyl (2S)-2-((3S)~3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.07g) in THF (0.5ml) was treated with diisopropyl azodicarboxylate 35 (0.06ml) , 3-furfuryl alcohol (0.030g) and tributylphosphine (0.075ml) and shaken at room temperature for 18h. The mixture was concentrated under reduced pressure and the residue purified by Biotage™ chromatography (eluting with cyclohexane:ethyl acetate 3:1) to give the title compound (0.015g) as a colourless gum. Mass spectrum: Found: MH+ 533 WO 02/100830 PCT/GB02/02721 43 Using similar chemistry, but selecting the appropriate starting materials the following were prepared: Intermediate 30 5 tert-Butvl f2S)-2-f(3S)-3-rr(6-chloro-2-naphthyl)sulfonyl](1.3-thiazol-2-vlmethvl)amino1-2-oxopvrrolidin-1 -vllpropanoate Mass spectrum: Found: MH+ 550 Intermediate 31 10 (2S)-2-l(3S)-3-rf(6-Chloro-2-naphthvl)sulfonvll(1.3-thiazol-2-vlmethvnaminol-2-oxopvrrolidin-1-vl)propanoic acid A solution of ferf-butyl (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](1,3-thiazol-2-ylmethyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.03g) in DCM (1ml) was treated with trifiuoroacetic acid (1ml) and stirred at room temperature for 1h. The solution was then 15 concentrated under reduced pressure to give the title compound (0.019g) as a colourless solid. Mass spectrum: Found: MH+ 494 Using similar chemistry, but selecting the appropriate starting materials the following were prepared: 20 Intermediate 32 f2S)-2-l(3S)-3-fF(6-Chloro-2-naphthvl)suifonvll(2-furvlmethvl)aminol-2-oxopvrrolidin-1-vllpropanoic acid mixture with (2SV2-((3S)-3-ff(6-chloro-2-naphthvllsulfonvnaminol-2-oxopvrrolidin-1-vllpropanoic acid (56:44) 25 Mass spectrum: Found: MH+ 478 Intermediate 33 ferf-Butvl 5-chloro-2-r(-ff3S)-1-r(1SV1-methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopyrrolidin-3-y|}amino)sulfonvn-1 H-indole-1 -carboxvlate 30 1-ferf-Butoxycarbonyl-5-chloroindole (0.1g) was dissolved in anhydrous THF (2ml) under nitrogen and cooled to -78°C. n-Butyllithium (1.6M in hexanes, 0.273ml) was added dropwise over 10min. After stirring at -78'C for 45min, sulphur dioxide gas was bubbled through the reaction for 5min. The reaction mixture was allowed to reach room temperature over 2h and concentrated under reduced pressure to give an off-white solid. The solid was 35 re-suspended in anhydrous DCM (2ml) and treated with N-chlorosuccinimide (0.0584g). The mixture was then stirred for 1h at room temperature and any remaining white solid removed by filtration. Half of this filtrate was treated with pyridine (0.017ml) and Intermediate 40 (0.022g). The reaction mixture was stirred at 40°C for 5h and then 72h at 30'C in a sealed vessel. The reaction mixture was washed with water, the organic phase 40 separated and dried (over magnesium sulphate), and evaporated under a stream of nitrogen WO 02/100830 PCT/GB02/02721 44 to give a residue which was purified by mass directed preparative h.p.i.c. to give the title compound (0.011g) as a colourless glass. Mass spectrum: Found: MH+ 555 5 Intermediate 34 N-((3SV1-f(1S)-1-Methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3-vllethenesulfonamide 2-Chloroethanesulfonyl chloride (0.284ml) was added dropwise to a mixture of Intermediate 40 (0.436g) and N,N-di-isopropylethylamine (0.938ml) in dry acetonitrile (6ml) at 0'C over 10 2min. The mixture was allowed to reach room temperature and stirred for 3 days, after which the reaction was quenched with water and concentrated under reduced pressure to give a brown residue. This residue was partitioned between ethyl acetate and water. The combined organic extracts were dried (over magnesium sulphate) and concentrated under reduced pressure to give a brown foam which was purified by SPE (silica, eluting with ethyl 15 acetatexyclohexane 1:1, ethyl acetate and then ethyl acetate:methanol 19:1) to give the title compound (0.227g) as a clear film. Mass Spectrum: Found: MH+ 332 Intermediate 35 20 ferf-Butvl (2S)-2-((3S)-3-(T(5'-chloro-2.2'-bithien-5-vl)sulfonvnamino)-2-oxopvrrolidin-1- vlbropanoate A solution of fert-butyi (2S)-2~[(3S)-3-amino-2-oxopyrrolidin-1-yl]propanoate (0.337g) in acetonitrile (20ml) was treated with triethylamine (0.41ml) and 5'-chloro-2,2'-bithiophene-5-sulfonyl chloride2 (0.372g) and stirred at room temperature for 17h. The mixture was 25 concentrated under reduced pressure and the residue purified using SPE (aminopropyl, eluting with methanol) to give the title compound (0.651 g) as a brown oil. Mass spectrum: Found: MH+ 491 Using similar chemistry and Intermediate 9, the following were prepared: 30 Intermediate 36 fe/f-Butvl (2SV2-f(3S)-3-(ff(E)-2-(4-chlorophenvnethenvnsulfonvl}amino)-2-oxopvrrolidin-1-vllpropanoate Mass spectrum: Found: MH+ 429 35 Intermediate 37 fe/f-Butvl (2SV2-r(3S)-3-W2-amino-2-oxoethvl)r(E)-2-(4- chlorophenvl)ethenvllsulfonvl>amino)-2-oxopvrrolidin-1-vnpropanoate Using Intermediate 36, and the synthetic procedure desaibed for Intermediate 22, the title compound was similarly prepared. 40 Mass spectrum: Found: MH+ 487 WO 02/100830 PCT/GB02/02721 45 Intermediate 38 ferf-Butvl (2S)-2-ff3S)-3-f(2-amino-2-oxoethvn(r(5'-chloro-2.2'-bithien-5-vnsulfonvnamino)-2-oxopyrrolidin-1 -vllpropanoate 5 Using Intermediate 35, and the synthetic procedure described for Intermediate 22, the title compound was similarly prepared. Mass spectrum: Found: MH+ 548 Intermediate 39 10 Benzyl (3SV1 -Id S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlcarbamate (2S)-2-((3S)-3-{[(Benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (84.5g) was dissolved in DMF (21) and 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (161g) was added, followed by N,N-diisopropylethylamine (92ml) and morpholine (46ml). The mixture was stirred under nitrogen for 2.5h, and saturated aqueous 15 ammonium chloride was added. The mixture was stirred for 15min then partitioned between water and ethyl acetate. The separated organic phase was washed with lithium chloride (10% by weight), followed by saturated sodium bicarbonate and brine. The organic layer was dried (over sodium sulphate) and concentrated under reduced pressure to give the title compound (65g) as a yellow solid. 20 Mass spectrum: Found: MH+ 376 Intermediate 40 (3S)-3-Amino-1 -IY1SV1 -methvl-2-morpholin-4-vl-2-oxoethvnpvrrolidin-2-one A mixture of benzyl (3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-25 ylcarbamate (20g), 10 % palladium on carbon (2g) and ethanol (1.31) was stirred under an atmosphere of hydrogen for 16h. The reaction mixture was filtered through Celite™ and the filtrate was concentrated under reduced pressure to give the title compound (12.3g) as a pale white oil. 1H NMR (D4MeOH): 85.05(1 H, dd), 3.59(9H, m), 3.37(2H, m), 2.42(1 H, m), 1.75(1H, m), 30 1,30(3H, d) ppm. Intermediate 41 ferf-Butvl (2SV2-((3S1-3-([(2-methvl-1.3-thiazol-4-vBmethvnaminoV-2-oxopvrrolidin-1-vltoropanoate 35 A solution of 2-methyl-1,3-thiazole-4-carbaldehyde (0.028g) in DCM (2ml) was treated with Intermediate 9 (0.05g) followed by acetic acid (0.013ml) and tetramethylammonium triacetoxyborohydride (0.116g), and the resultant mixture stirred at room temperature for 66h. The reaction mixture was partitioned between water and DCM. The organic layer was separated, dried (over magnesium sulphate) and concentrated under reduced pressure to 40 give the title compound (0.07g) as an oil. WO 02/100830 PCT/GBO2/02721 46 Mass spectrum: Found: MH+ 340 Using similar chemistry, but selecting the appropriate starting materials the following were prepared: 5 Intermediate 42 tert-Butvl (2SV24(3SV2-oxo-3-r(pvridin-4-vlmethvnamino1pvrrolidin-1-vl}propanoate Mass spectrum: Found: MH+ 320 Intermediate 43 10 ferf-Butvl (2SV24f3S')-2-oxo-3-[fpvridin-2-vlmethvl')aiTiino1pvrrolidin-1-vllpropanoate Mass spectrum: Found: MH+ 320 Intermediate 44 terf-Butvl (2SV2-((3SV3"ff(6-chloro-2-naphthvnsulfonvllf(2-methvl-1.3-thiazol-4-15 vl)methvnamino}-2-oxopvrrolidin-1-vltoropanoate Using Intermediate 41 and the synthetic procedure described for Intermediate 14, the title compound was similarly prepared. Mass spectrum: Found: MH+ 564 20 Intermediate 45 ferf-Butvl (2S)-2-((3S)-3-rK6-chloro-2-naphthvl)sulfonvll(pyridin-4-vlmethvnamino1-2-oxopvrrolidin-1 -vDpropanoate Using Intermediate 42 and the synthetic procedure described for Intermediate 14, the title compound was similarly prepared. 25 Mass spectrum: Found: MH+ 544 Intermediate 46 ferf-Butvl (2SV2-ff3S)-3-rr(6-chloro-2-naphthvhsulfbnvn(pvridin-2-vlmethvnamino1-2-oxopvrroiidin-1-vitoropanoate 30 Using Intermediate 43 and the synthetic procedure described for Intermediate 14, the title compound was similarly prepared. Mass spectrum: Found: MH+ 544 Intermediate 47 35 (2SV2-((3SV3-(r(6-Chloro-2-naphthvnsulfonvlir(2-methvl-1.3-thiazol-4-vl)methvnaminoV2-oxopvrrolidin-1 -vllpropanoic acid Using Intermediate 44 and the synthetic procedure described for Intermediate 13, the title compound was similarly prepared. Mass spectrum: Found: MH+ 508 40 WO 02/100830 PCT/GB02/02721 47 Intermediate 48 (2SV24(3SV3-fr(6-Chloro-2-naphthvl)sulfonvll(pvridin-4-vlmethvl)amino1-2-oxopvrrolidin-1-vllpropanoic acid hydrochloride Using Intermediate 45 and the synthetic procedure described for Intermediate 13, the title 5 compound was similarly prepared. Mass spectrum: Found: MH+ 488 Intermediate 49 (2S)-2-f(3SV-3-rr("6-Chloro-2-naphthvnsulfonvn(pvridin-2-vlmethvl)amino1-2-oxopvrrolidin-1-10 vftpropanoic acid hydrochloride Using Intermediate 46 and the synthetic procedure described for Intermediate 13, the title compound was similarly prepared. Mass spectrum: Found: MH+ 488 15 Intermediate 50 5-Chloro-1 -benzofuran To a solution of 5-chloro-1-benzofuran-2-carboxylic acid (0.2g) in 1-methyl-2-pyrrolidinone (2ml) was added copper granules (0.2g). The reaction mixture was heated at 250°C for 3.5min in a microwave. The reaction vessel was cooled to room temperature and the mixture 20 combined with four other similar mixtures and the combined mixtures partitioned between water and diethyl ether. The organic layer was washed with water and brine, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (0.65g) as a yellow oil. Gas-chromatography electron-ionisation spectrum: Found: M+152, Rt 5.72min 25 Intermediate 51 5-Chloro-1 -benzofuran-2-sulfonvl chloride n-Butyl lithium (1.6M in hexanes, 0.045ml) was added to a cooled (-78°C) solution of intermediate 50 (0.11g) in anhydrous thf (5ml) over 5min. The reaction was stirred for a 30 further 5min, warmed to -45°C and stirred for 40min. The mixture was cooled to -70°C and sulphur dioxide gas bubbled into the vessel over 7min. The solution was allowed to warm to room temperature over 45min, and then concentrated under reduced pressure to give a yellow gum. To a suspension of the gum in anhydrous DCM (4ml) was added N-chlorosuccinimide (0.118g) and the mixture stirred at room temperature for 75min. The 35 solution was filtered, and the filtrate concentrated under reduced pressure to give the title compound (0.093g) as a yellow solid. Mass Spectrum: Found: MH+ 260 Intermediate 52 40 2-Chloro-4-ethenvlPhenol WO 02/100830 PCT/GB02/02721 48 To a slurry of methyltriphenylphosphonium bromide (0.23g) in dry THF (5ml) under nitrogen at -78°C , n-butyl lithium (1.6M in hexanes, 0.37ml) was added dropwise over 2min. The mixture was allowed to warm to 0 °C, stirred for 20min, cooled to -78 °C and a solution of 3-chloro-4-[[(1,1-dimethylethyl)dimethyIsilyl]oxy]benzaldehyde* (0.134g) in dry THF (5ml) 5 added. The reaction mixture was allowed to reach room temperature overnight and quenched with saturated aqueous ammonium chloride. The resultant mixture was extracted with diethyl ether and the combined organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane, followed by 5% to 25% ethyl acetate:cyclohexane) to give the title compound (0.049g) as an oil. 10 H.p.l.c. (1) Rt 3.26min *Boukouvalas, J; Maltais, F; Lachance, N., Tetrahedron Lett. (1994), 35(43), 7897-900. Intermediate 53 fe/f-Butvl (2-chloro-4-vinvlphenoxv')diphenvlsilane 15 A mixture of Intermediate 52 (0.038g), imidazole (0.042g) and ferf-butyldiphenylsilyl chloride (0.083ml) was stirred in dry DMF (0.5ml) at room temperature under nitrogen for 20h. The mixture was quenched with water, extracted with diethyl ether, dried (over magnesium sulphate), filtered and concentrated under reduced pressure. The resultant oil was purified using SPE (silica, eluting with cyclohexane followed by 5% to 20% ethyl 20 acetate:cyclohexane) to give the title compound (0.102g) as an oil. H.p.l.c. (1) Rt 4.71 min Intermediate 54 3-([terf-Butvl(dimethvnsiivlloxvV4-chlorobenzaldehvde 25 A mixture of 4-chloro-3-hydroxy-benzaldehyde* (0.354g), 4-N,N-dimethylaminopyridine (0.028g), tert-butyldimethylsilyI chloride (0.409g) and triethylamine (0.473ml) in DCM (15ml) was stirred at room temperature under nitrogen for 19h. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with diethyl ether. The combined organic extracts were concentrated under reduced pressure to give an oil which was purified 30 using SPE (silica, eluting with cyclohexane followed by 10% to 30% ethyl acetate:cyclohexane) to give the title compound (0.42g) as an oil. ' H.p.l.c. (1) Rt4.11min *Kel!ey, J; Linn, J; Selway, J. W. T., J. Med. Chem. (1989), 32(8), 1757-63. 35 Intermediate 55 (EV2-(3-ffferf-Butvl(diphenvnsilvfloxvM-chlorophenvlY-N-{(3SV1-f(1SV1-methvl-2-morphorin- 4-vl-2-oxoethvl1-2-oxopyrrolidin-3-vllethenesulfonamide Sulphuryl chloride (0.103ml) was added dropwise to DMF (0.116ml) at 0°C under nitrogen, over 5min. The mixture was allowed to reach room temperature and stirred for 30min. 40 Intermediate 57 (0.293g) in cyclohexane (0.2ml) was added in one portion and the resultant WO 02/100830 PCT/GB02/02721 49 mixture was heated at 90 °C for 6h. The cooled mixture was poured onto crushed ice, extracted with diethyl ether, dried (over sodium sulphate) and concentrated under reduced pressure. This crude sulfonyl chloride was treated with Intermediate 40 (0.134g), 4-dimethylaminopyridine (0.0068g), N.N'-di-isopropylethylamine (0.192ml) in dry DCM (5ml), 5 and after stirring for 3 days at room temperature under nitrogen, the mixture was concentrated under reduced pressure. The resultant solution was washed with water and filtered through a hydrophobic frit. The filtrate was concentrated under reduced pressure to give an oil, which was purified by SPE (silica, eluting with cyclohexane:ethyl acetate 19:1 and then 10:1) followed by mass directed preparative h.p.l.c. to give the title compound 10 (0.0078g) as a colourless gum. Mass spectrum: Found: MH+ 696 Intermediate 56 2-Chloro-5-vinvlphenol 15 The title compound was prepared using intermediate 54 and the synthetic procedure described for Intermediate 52. H.p.l.c. (1) Rt3.22min Intermediate 57 20 ferf-Butvl(2-chloro-5-vinvlphenoxv)diphenvlsilane The title compound was prepared using Intermediate 56 and the synthetic procedure described for Intermediate 53. H.p.l.c. (1) Rt4.68min 25 Intermediate 58 (3SV3-(r(6-Chloro-1 .S-benzothiazol^-vDthiolaminol-l-IYISI-l -methvl-2-morpholin-4-vl-2-oxoethvnpvrrolidin-2-one N-Chlorosuccinimide (0.37g) was added to 4-chloro-2-mercaptobenzothiazole (0.5g) in DCM (15mi) under nitrogen, and stirred at room temperature for 3h. A solution of Intermediate 40 30 (0.569g) and triethylamine (1.04ml) in anhydrous DCM (5ml) were added and the resulting mixture stirred at room temperature under nitrogen for 2h. The solution was filtered and the filtrate was diluted with DCM. The organic solution was washed with water and brine, dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified by SPE (silica, eluting with cyclohexane: ethyl acetate 1:1 increasing polarity to ethyl 35 acetate:methanol 19:1) to give the title compound (0.3g) as a white solid. Mass spectrum: Found: MH+ 441 Intermediate 59 5-Chlorothienor2.3-b1pvridine-2-sulfonvl chloride WO 02/100830 PCT/GB02/02721 50 n-Butyl lithium (1.6M in hexanes, 0.37ml) was added to a cooled (-78°C) solution of 5-chlorothieno[2,3-b]pyridine* (0.1 OOg) in anhydrous THF (5ml) over 15min. The reaction was stirred for a further 5min, warmed to -45°C and stirred for 40min. The mixture was cooled to -70°C and sulphur dioxide gas was bubbled into the vessel over 10min. The reaction was 5 allowed to reach room temperature over 45min, and then concentrated under reduced pressure. The residue was dissolved in anhydrous DCM (5ml), treated with N-chlorosuccinimide (0.097g) and stirred at room temperature for 75min. The solution was filtered, and the filtrate concentrated under reduced pressure to give the title compound (0.198g) as a yellow solid. 10 Mass Spectrum: Found: MH+ 277 for dimethylamine quenched mass spectrum sample *Klemm. L.H. et.al., J. Heterocycl. Chem. (1968), 5(6), 773-8. Intermediate 60 5-Chlorothienor3.2-b1pvridine-2-sulfonvl chloride 15 5-Chlorothieno[3,2-b]pyridine* (0.2g) was dissolved in anhydrous THF (10ml) under nitrogen and cooled to -70°C. /7-Butyllithium (1.6M in hexanes, 0.780ml) was added dropwise over 10min and the mixture stirred for a further 5min. The mixture was warmed to -50'C and stirred for 55min. The reaction was cooled to -70"C, and sulphur dioxide gas was bubbled through the reaction for 10min. The reaction was allowed to warm to room temperature and 20 concentrated under reduced pressure to give a yellow residue which was re-suspended in anhydrous DCM (6ml) and treated with N-chlorosuccinimide (0.189g). The mixture was stirred for 2h at room temperature and any remaining solid removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (0.153g) as a white solid. 25 Mass Spectrum: Found: MH+ 277 for dimethylamine quenched mass spectrum sample *Barker. J.N, et.al.f J. Chem. Res. (1984), (3), 771-795. Example 1 6-Chloro-N-((3S)-1-rnS)-l-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-30 vl)naphthalene-2-sulfonamide To a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 17] (0.105g) in DCM (10ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.152g), HOBT (0.107g) and triethylamine (0.222ml) and the mixture was stirred at room temperature for 30min. 35 Morpholine (0.07ml) was added and the resultant mixture stirred at room temperature for 16h. The mixture was partitioned between DCM and water. The aqueous layer was re-extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane:ethyl acetate 5:1, and ethyl acetate) to give the title compound 40 (0.1g) as a white solid. WO 02/100830 PCT/GB02/02721 51 Mass spectrum: Found: MH+ 466 H.p.l.c. (1) Rt3.13min 1H NMR (D4MeOH): 5 8.54(1 H, br.s), 8.08-7.96(4H, m), 7.63(1 H, dd), 5.00(1 H, q), 4.18(1 H, dd), 3.69-3.46(9H, m), 3.31-3.29(1 H, m), 2.27(1 H, m), 1.77(1H, m), 1.26(3H, d) ppm. 5 Using similar chemistry, but selecting the appropriate staring materials the following were prepared: Example 2 6-Chloro-N-f(3SV1-f(1SV2-(2.6-dimethvlmorpholin-4-vh-1-methvl-2-oxoethvll-2-10 oxopyrrolidin-3-vl>naphthalene-2-sulfonamide Mass spectrum: Found: MH+ 494 H.p.l.c. (1) Rt3.16min Example 3 15 6-Chloro-N-f(3S)-1-r(1Syi-methvl-2-(3-methvlmorpholin-4-v0-2-oxoethvH-2-oxopvrrolidin-3-vllnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 480 H.p.l.c. (1) Rt3.23min 20 Example 4 6-Chloro-N-(,(3S)-1-f{1S')-1-methvl-2-oxo-2-f3-(pvrrolidin-1-vlcarbonvnmorpholin-4-vnethvll- 2-oxopyrrolidin-3-vBnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt3.08min 25 Example 5 6-Chloro-N-r (3S)-1 -((1SV1 -methvl-242-f (methvlsulfonvOmethvll morpholi n-4-y])-2-oxoeth vIV 2-oxopvrrolidin-3-vnnaphthalene-2-sulfonamide Mass specirum: Found: MH+ 558 30 H.p.l.c. (1)Rt3.17min Example 6 6-Chloro-N-((3S>1 -((1 S)-2-r2-( methoxvmethvhmorpholin-4-vn-1 -methvl-2-oxoethvl)-2-oxopvrrolidin-3-vPnaphthalene-2-sulfonamide 35 Mass spectrum: Found: MH+ 510 H.p.l.c. (1) Rt 3.02min Example 7 and Example 8 4-r(2S)-2-((3S>-3-(r(6-Chloro-2-naphthvl)sulfonvnaminoy2-oxopvrrolidin-1-v0propanovn-N-40 methvlmorpholine-2-carboxamide [Isomer 1 and Isomer 21 WO 02/100830 PCT/GB02/02721 52 Isomer 1 Mass spectrum: Found: MH+ 523 H.p.l.c. (1)Rt2.93min Isomer 2 5 Mass spectrum: Found: MH+ 523 H.p.l.c. (1) Rt2.96min Example 9 6-Chloro-N-((3Sn-f(1S)-1-methvl-2-oxo-2-r2-(pvrrolidin-1-vicarbonvDmorpholin-4-vHethviy 10 2-oxopvrrolidin-3-vnnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt3.04min Example 10 15 4-r(2S)-2-((3S)-3-(r(6-Chloro-2-naphthvnsulfonvllamino)-2-oxopvrrolidin-1-vl)propanovn-N.N-dimethvlmorpholine-2-carboxamide Mass spectrum: Found: MH+ 537 H.p.l.c. (1) Rt2.96min 20 Example 11. Example 12 and Example 13 4-r(2S)-2-(f3S)-3-irf6-Chloro-2-naphthvDsulfonvnamino)-2-oxopvrrolidin-1-yl)propanovn-N-(2-hvdroxypropyl)morpholine-2-carboxamide [Isomer 1. Isomer 2 and Isomer 31 Isomer 1 Mass spectrum: Found: MH+ 567 25 H.p.l.c. (1)Rt2.92min Isomer 2 Mass spectrum: Found: MH+ 567 H.p.l.c. (1) Rt 2.91 min isomer 3 30 Mass spectrum: Found: MH+ 567 H.p.l.c. (1) Rt2.92min Example 14 4-r(2S)-2-((3Sy3-ir(6-Chloro-2-naphthvhsulfonvnaminoy-2-oxopvrrolidin-1-vl)propanovn-N.N-35 diisopropvlmorpholine-2-carboxamide Mass spectrum: Found: MH+ 593 H.p.l.c. (1) Rt3.4min Example 15 WO 02/100830 PCT/GB02/02721 53 6-Chloro-N-^3S)-1-(nS)-1-methvl-2-oxo-2-r2-(piperidin-1-vlcarbonvl)morpholin-4-vl1ethvl)-2- oxopvrrolidin-3-vnnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 577 H.p.l.c. (1) Rt 3.21 min 5 Example 16 6-Chloro-N-r(3S)-1-((1SH-methvl-242-f(methvlamino)methvnmorpholin-4-vl)-2-oxoethvD-2-oxopvrrolidin-3-vnnaphthalene-2-sulfonamide formate Mass spectrum: Found: MH+ 509 10 H.p.l.c. (1)Rt2.58min Example 17 6-Chloro-N-((3S)-1-{(1S)-1-methvl-2-oxo-2-[2-(pvrrolidin-1-vlmethvl')morpholin-4-vnethvl)-2-oxopvrrolidin-3-v0naphthalene-2-sulfonamide formate 15 Mass spectrum: Found: MH+ 549 H.p.l.c. (1) Rt2.58min Example 18 6-Chloro-N4(3S)-1-f(1S)-2-(2-(r(2-hvdroxvpropvl)aminolmethvllmorpholin-4-vl)-1-methvl-2-20 oxoethvfl-2-oxopvrrolidin-3-vl>naphthalene-2-sulfonamide formate Mass spectrum: Found: MH+ 553 H.p.l.c. (1)Rt2.55min Example 19 and Example 20 25 6-Chioro-N-f(3SM-((1Sy2-(2-r(dimethvlamino)methvnmorpholin-4-vlH-methvl-2-oxoethvD-2-oxopvrrolidin-3-vnnaphthalene-2-sulfonamide formate fisomer 1 and Isomer 21 Isomer 1 Mass spectrum: Found: MH+ 523 H.p.i.c. (1) Rt2.54min 30 Isomer 2 Mass spectrum: Found: MH+ 523 H.p.l.c. (1)Rt2.55min Example 21 35 6-Chloro-N-r(3S)-1-((1S)-2-f2-Kdiisopropvlamino)methvl1morpholin-4-vl)-1-methyl-2-oxoethvD-2-oxopvrrolidin-3-vHnaphthalene-2-sulfonamide formate Mass spectrum: Found: MH+ 579 H.p.l.c. (1) Rt 2.67min 40 Example 22 WO 02/100830 PCT/GB02/02721 54 6-Chloro-N-((3SV14(1 SV1-methyl-2-oxo-242-(piperidin-1 -vlmethv0morpholin-4-vllethvl)-2-oxopvrrolidin-3-vl)naphthalene-2-sulfonamide formate Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt2.62min 5 Example 23 6-Chloro-N-((3SV1-f(1S)-2-r(2R.6S"l-2.6-dimethvlmorpholin-4-vll-1-methvl-2-oxoethvl)-2-oxopvrrolidin-3-vDnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 494 10 H.p.l.c. (1)Rt 3.15min Example 24 6-Chloro-N4(3R V-1 -f(1 SV1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vllnaphthalene-2-sulfonamide 15 Mass spectrum: Found: MH+ 466 H.p.l.c. (1) Rt2.96min Example 25 5'-Chloro-N-i(3S)-1-r(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvl]-2-oxopyrrolidin-3-vl}-2.2'-20 bithiophene-5-sulfonamide 'ferf-Butyl (2S)-2-((3S)-3-{[(5'-chloro-2,2,-bithien-5-yl)sulfonyI]amino}-2-oxopyrrolidin-1-yl)propanoate [Intermediate 35] (0.217g) was dissolved in DCM (2ml) and treated with trifiuoroacetic acid (2ml) and stirred at room temperature for 2h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently dissolved in 25 DCM (5ml) and treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.256g), HOBT (0.184g) and triethylamine (0.375ml). After the solution had been stirred at room temperature for 30min, morpholine (0.117ml) was added and the resultant mixture stirred for a further 20h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM and water. The organic component was washed with 30 water and brine, and concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane; cyclohexane:ethyl acetate 4:1, 1:1,1:4; ethyl acetate; methanol:ethyl acetate 1:10; methanol) to give the title compound (0.078g) as a white solid. Mass spectrum: Found: MH+ 504 H.p.l.c. (1) Rt 3.17min 35 1H NMR (D4MeOH): 8 7.61 (1H, d), 7.23(1 H, d), 7.22(1 H, d), 7.03(1 H, d), 5.04(1 H, q), 4.21 (1H, dd), 3.69-3.46(9H, m), 3.39-3.35(1 H, m), 2.39(1 H, m), 1.86(1H, m), 1.30(3H, d) ppm. Example 26 WO 02/100830 PCT/GB02/02721 55 (EV2-(4-ChlorophenvlVN-4(3S)-1-r( 1SV1 -methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3-vltethenesulfonamide Using Intermediate 36 and the synthetic procedure described for Example 25, the title compound was prepared. 5 Mass spectrum: Found: MH+ 442 H.p.l.c. (1)Rt2.86min 1H NMR (CDCI3):5 7.46(1 H, d), 7.44(2H, d), 7.38(2H, d), 6.89(1 H, d), 5.35(1 H, br.d), 5.05(1 H, q), 4.00(1 H, m), 3.69-3.48(9H, m), 3.35(1 H, m), 2.62(1 H, m), 2.06(1 H, m), 1.33(3H, d) ppm. 10 Example 27 N2-ir(E)-2-(4-Chlorophenvl)ethenvnsulfonvl)-N2-(f3S)-1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl>alvcinamide Using Intermediate 37 and the synthetic procedure described for Example 25, the title 15 compound was prepared. Mass spectrum: Found: MH+ 499 H.p.l.c. (1) Rt 2.81 min Example 28 20 N2-K5'-Chloro-2.2'-bithien-5-vnsulfonvn-N2-l(3Sy 1 -K1 SV1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopyrrolidin-3-vl)qlvcinamide Using Intermediate 38 and the synthetic procedure described for Example 25, the title compound was prepared. Mass spectrum: Found: MH+ 561 25 H.p.l.c. (1)Rt2.96min Example 29 5'-Chloro-N-(cvanomethvn-N-((3S)-1-f(1SV-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxoPvrrolidin-3-vli-2.2'-bithiophene-5-sulfonamide 30 Using Example 25 and the synthetic procedure described for Example 50, the title compound was prepared. Mass spectrum: Found: MH+ 543 H.p.l.c. (1)Rt3.34min Using similar chemistry, but selecting the appropriate staring materials the following were 35 prepared: Example 30 Methyl N-f(5'-chloro-2.2'-bithien-5-vl)sulfonvn-N-((3SH-f(1SM-methyl-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3-vl}qlvcinate 40 Mass spectrum: Found: MH+ 576 WO 02/100830 PCT/GB02/02721 56 H.p.l.c. (1)Rt3.34min Example 31 5'-Chloro-N-f(3SV 1 -f( 1 S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopyrrolidin-3-vl)-N-(2-5 oxobutvn-2.2'-bithiophene-5-sulfonamide Mass spectrum: Found: MH+ 574 H.p.l.c. (1)Rt3.4min Example 32 10 N-r(5'-Chloro-2.2'-bithien-5-vnsulfonvll-N-((3SV1-r(1S)-1-methvl-2-morpholin-4-vl-2-oxoeth vn-2-oxopyrrol id in-3-vl)g I vci ne Using standard alkaline hydrolysis conditions, the title compound was prepared from Example 30. Mass spectrum: Found: MH+ 562 15 H.p.l.c. (1) Rt3.21min Example 33 (E)-2-(4-ChlorophenvD-N-(cvanomethvl>N-{(3S)-1-r(1Syi-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopyrrolidin-3-vllethenesulfonamide 20 Using Example 26 and bromoacetonitrile, and the synthetic procedure described for Example 50, the title compound was prepared. Mass spectrum: Found: MH+ 481 H.p.l.c. (1) Rt 3.05min Using similar chemistry, but selecting the appropriate starting materials the following were 25 prepared: Example 34 (E)-2-(4-Chlorophenvl)-N-f(3S)-1 -f( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxouvrroiiuiri-3-viVN-(2-oxobutvi')ethenesuifonamide 30 Mass spectrum: Found: MH+ 512 H.p.l.c. (1) Rt3.13min Example 35 Methvl N-(rfEV2-f4-chlorophenvl')ethenvl1sulfonvl>-N-{(3SV1 -[(1 SV1-methvl-2-morpholin-4-vl-35 2-oxoethvn-2-oxopvrrolidin-3-vl)qlvcinate Mass spectrum: Found: MH+ 514 H.p.l.c. (1) Rt3.05min Example 36 WO 02/100830 PCT/GB02/02721 57 N4F(E)-2-(4-Chlorophenyl)ethenynsulfonvl)-N4(3S)-14(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlkilvcine Using standard alkaline hydrolysis conditions, the title compound was prepared from Example 35. 5 Mass spectrum: Found: MH+ 500 H.p.l.c. (1) Rt2.9min Example 37 6-Chloro-N-(3-furvlmethvlVN-f(3SV1-f(1SV1-methvl-2-morpholin-4-vl-2-oxoethvH-2-10 oxopvrrolidin-3-vl}naphthalene-2-sulfonamide A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide [Example 1] (0.015g) in THF (0.5ml) was treated with diisopropyl azodicarboxylate (0.01ml), 3-furanmethanol (0.004ml) and tri-n-butylphosphine (0.008ml) and shaken at room temperature for 60h. The mixture was concentrated under 15 reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.015a) as a colourless gum. Mass spectrum: Found: MH+ 546 H.p.l.c. (1) Rt3.33min Using similar chemistry, but selecting the appropriate starting materials the following were 20 prepared: Example 38 6-Chloro-N-((3S)-14(1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vlV N-(pvridin-3-vlmethvDnaohthalene-2-sulfonamide formate 25 The title compound was isolated from a crude reaction mixture using mass directed preparative h.p.l.c. Mass spectrum: Found: MH+ 557 H.p.l.c. (1)Rt2.9min 30 Example 39 6-Chloro-N-ethvl-N4(3S)-14( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3- vDnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 494 H.p.l.c. (1) Rt3.32min 35 Example 40 6-Chloro-N4(3S)-1-r(1SV1-methvl-2-moraholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl>-N42-oxobutvl)naphthalene-2-sulfonamide To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-oxobutyl)amino]-2-40 oxopyrrolidin-1-yl}propanoic acid [Intermediate 25] (0.035g) in DCM (2ml) were added 1-[3- WO 02/100830 PCT/GB02/02721 58 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.044g), HOBT (0.031g) and triethylamine (0.064ml) and the mixture was stirred at room temperature for 30min. Morpholine (0.02ml) was added and the resultant mixture stirred at room temperature for 16h. The mixture was partitioned between DCM and water. The aqueous layer was re-5 extracted with DCM and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.008g) as a white solid. Mass spectrum: Found: MH+ 536 H.p.l.c. (1) Rt3.20min 10 Using similar chemistry, but selecting the appropriate starting materials the following were prepared: Example 41 N-2-i(6-Chloro-2-naphthvnsulfonvll-N-2-((3SV1-[(1SV1-methvl-2-morpholin-4-vl-2-oxoethvll-15 2-oxopvrroiidin-3-vl)qlvcinamide The title compound was prepared from Intermediate 26. Mass spectrum: Found: MH+ 523 H.p.l.c. (1) Rt 2.87min 20 Example 42 6-Chloro-N-(2-furvlmethvl)-N-((3S)-1-R1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)naphthalene-2-sulfonamide The title compound was prepared from Intermediate 32. Mass spectrum: Found: MH+ 546 25 H.p.l.c. (1) Rt 3.33min Example 43 6-Chloro-N-lf3S)-1 -f( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopyrrolidin-3-vl)-N-( 1,3-thiazol-2-vlmethvl)naphthalene-2-sulfonamide 30 The title compound was prepared from Intermediate 31. Mass spectrum: Found: MH+ 563 H.p.l.c. (1) Rt3.18min Example 44 35 N2-r(6-Chloro-2-naphthvl)sulfonvlI-N2-((3S)-1-fl 1 S)-2-K2R.6S)-2.6-dimethvlmorpholin-4-vn-1-methvl-2-oxoethvl>-2-oxopvrrolidin-3-vl)qlvcinamide The title compound was prepared from Intermediate 26. Mass spectrum: Found: MH+ 551 H.p.l.c. (3) Rt 13.4min WO 02/100830 PCT/GB02/02721 59 Example 45 6-Chloro-N-l(3Syi-r(1S1-1-methvl-2-morDholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlV-N-r(2-methvl-1.3-thiazol-4-vnmethvnnaphthalene-2-sulfonamide The title compound was prepared from Intermediate 47. 5 Mass spectrum: Found: MH+ 577 H.p.l.c. (1)Rt3.24min Example 46 6-Chloro-N~ff3SV 1 -f (1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)-N-10 (pyridin-2-vlmethvl)naphthalene-2-sulfonamide formate The title compound was prepared from Intermediate 49. Mass spectrum: Found: MH+ 563 H.p.l.c. (1)Rt3.62min 15 Example 47 6-Chloro-N-l (3SV1 -f (1S1-1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-viy N-(pvridin-4-vlmethvnnaphthalene-2-sulfonamide formate The title compound was prepared from Intermediate 48. Mass spectrum: Found: MH+ 557 20 H.p.l.c. (1)Rt2.83min Example 48 6-Chloro-N-f(3S)-1-ff1R)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vllnaphthalene-2-sulfonamide 25 To a solution of (2R)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid [Intermediate 28] (0.037g) in DCM (1.0ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.036g), HOBT (0.025g) and triethylamine (0.026ml) and the mixture was stirred at room temperature for 5min. Morpnoiine (0.012mi) was added and the resultant mixture stirred at room temperature for 30 15.5h. The mixture was partitioned between DCM and saturated sodium bicarbonate solution and then passed through a hydrophobic frit. The organic extract was concentrated under reduced pressure and the residue was partially purified using preparative thin layer chromatography (20cm x 20cm 1mm thick Whatman PKF256 Si02 plate, eluting with hexane:ethyl acetate 1:5) to give an impure sample of the title compound. This sample was 35 repurified using preparative thin layer chromatography (20cm x 20cm 1mm thick Whatman PKF256 Si02 plate, eluting with hexane:ethyl acetate 1:8) to give the title compound (0.036g) as a white solid. Mass spectrum: Found: MH+ 466 H.p.l.c. (1) Rt2.95min 40 WO 02/100830 PCT/GB02/02721 60 Example 49 6-Chloro-N-methvl-N-f(3S)-1 -IY 1R V1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vl)naphthalene-2-sulfonamide The title compound was prepared using Intermediate 27 and the synthetic procedure 5 described for Example 1. Mass spectrum: Found: MH+ 479 H.p.l.c. (1) Rt3.18min Example 50 10 6-Chloro-N-(cvanomethvlVN-ff3SV1-r(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vllnaphthalene-2-sulfonamide A solution of 6-chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide [Example 1] (0.01 g) in THF (2ml) was cooled to -78'C under nitrogen, and treated with lithium bis(trimethylsilyl) amide (1.0M solution in THF; 0.026ml), 15 followed by bromoacetonitrile (0.013g). The resultant solution was allowed to reach room temperature and stirred for a further 16h. The mixture was then cooled to -78'C and further lithium bis(trimethylsiiyl) amide (0.026I) added. After reaching room temperature, the reaction mixture was stirred for a further 18h and then quenched by the addition of methanol (1ml). The resultant solution was concentrated under reduced pressure and the residue 20 purified by mass directed preparative h.p.l.c. to give the title compound (0.003g) as a white solid. Mass spectrum: Found: MH+ 505 H.p.l.c. (1)Rt3.16min Similarly prepared using commercially available alkyl halides, were: 25 Example 51 6-Chloro-N-methvl-N-~(Y3S)-1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethyn-2-oxopvrrolidin-3-vllnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 480 30 H.p.l.c. (1) Rt 3.11 min Example 52 6-Chloro-N-f3.3-dimethvl-2-oxobutvl)-N-f(3S)-1-r(1S)-1-methvl-2-morDholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)naphthalene-2-sulfonamide 35 Mass spectrum: Found: MH+ 564 H.p.l.c. (1)Rt3.39min Example 53 N2-f(6-Chloro-2-naphthvDsulfonvn-N1-methvl-N24(3Syi-r(1SV1-methvl-2-iTiorpholin-4-vl-2-40 oxoethvll-2-oxoDvrrolidin-3-vlkilvcinamide WO 02/100830 PCT/GB02/02721 61 Mass spectrum: Found: MH+ 537 H.p.l.c. (1)Rt2.98min Example 54 5 N-Allvl-6-chloro-N-((3SV1-r(1S1-1-methv[-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3-vl)naphthalene-2-sulfonamide Mass spectrum: Found: MH+ 506 H.p.l.c. (1) Rt3.26min 10 Example 55 Methyl N4(6-chloro-2-naphthy0sulfonvfl-N4('3S)-1-r(1S)-1-methvl-2-morpholin-4-vl-2- oxoethvll-2-oxopvrrolidin-3-vl}glvcinate Mass spectrum: Found: MH+ 538 H.p.l.c. (1) Rt3.12min 15 Example 56 Ethyl N-r(6-chloro-2-naphthvnsulfonvl1-N-l(3SV1-f(1S)-1-methvl-2-morpholin-4-vl-2- oxoethvn-2-oxopvrrolidin-3-vl>alvcinate Mass spectrum: Found: MH+ 552 20 H.p.l.c. (1)Rt3.36min Example 57 ferf-Butvl N4(6-chloro-2-naphthv0sulfonvl1-N-l(3S)-1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl}qlvcinate 25 Mass spectrum: Found: MH+ 580 H.p.l.c. (1) Rt3.45min Example 58 N-f('6-Chioro-2-naphthvr)sulfonvll-N-{(3S)-1 -K1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-30 oxopvrrolidin-3-vllalvcine To a solution of methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate [Example 55] (0.010g) in THF (2ml) was added lithium hydroxide (0.003g) in water (2ml), and the resultant solution stirred for 16h. The mixture was acidified to pH5 using hydrochloric acid (2N), and then concentrated 35 under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.006g) as a white solid. Mass spectrum: Found: MH+ 524 H.p.l.c. (1) Rt 3.OOmin 40 Example 59 WO 02/100830 PCT/GB02/02721 62 6-Chloro-N-( (3RV1 -f (1RV1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxoDvrrolidin-3-vl)naphthalene-2-sulfonamide Using Intermediate 19 and the procedure described for Example 1, the title compound was prepared. 5 Mass spectrum: Found: MH+ 466 H.p.l.c. (1) Rt2.95min Example 60 5-Chloro-N-f(3Syi-r(1SM-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlM-10 benzofuran-2-sulfonamide To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one [Intermediate 40] (0.077g) in anhydrous acetonitrile (2ml) were added 5-chloro-1~ benzofuran-2-sulfonyl chloride [Intermediate 51] (0.043g) in acetonitrile (2ml) and pyridine (0.057ml), and the mixture was stirred at room temperature for 72h. Saturated ammonium 15 chloride solution (2ml) was added and the resultant mixture stirred at room temperature for 20min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and hydrochloric acid (2M). The organic layer was washed with saturated sodium bicarbonate and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound 20 (0.043g) as a white solid. Mass spectrum: Found: MH+ 456 H.p.l.c. (1) Rt2.78min Example 61 25 (EV2-(5-Chlorothien-2-vl)-N4(3S)-1 -[(1S1-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vllethenesulfonamide Route 1 To a solution of (3S)-3-amino-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]pyrrolidin-2-one [intermediate 40] (14.9g) in anhydrous acetonitriie (750mi) were added (E)-2-(5-chlorothien-30 2-yl)ethenesulfonyl chloride (16.5g) in acetonitrile (250ml) and pyridine (11ml), and the mixture was stirred at room temperature for 72h. Saturated ammonium chloride solution was added and the resultant mixture stirred at room temperature for 30min. The mixture was concentrated under reduced pressure and the residue partitioned between chloroform and a 1:1 mixture of hydrochloric acid (2M) and water. The organic layer was washed with a 1:1 35 mixture of saturated sodium bicarbonate and water, and brine. The organic layer was isolated, dried (over magnesium sulphate) and concentrated under reduced pressure to give the title compound (19.3g) as a white solid. Mass spectrum: Found: MH+ 448 H.p.l.c. (1) Rt 2.99min i WO 02/100830 PCT/GB02/02721 63 1H NMR (CDCI3):8 7.48(1 H, d), 7.08(1 H, d), 6.90(1 H, d), 6.55(1 H, d), 5.12(1H, br.d), 5.06(1 H, q), 3.96(1 H, m), 3.70-3.48(9H, m), 3.35(1 H, m), 2.62(1 H, m), 2.05(1 H, m), 1.34(3H, d) ppm. Route 2 5 To a mixture of Intermediate 34 (0.028g), tris(dibenzylideneacetone)dipal!adium (0) (0.0028g) and 2-(di-f-butylphosphino)biphenyl (0.0037g) under nitrogen, was added dry dioxan (0.25ml) and the mixture was stirred for 5min at room temperature. N,N-Di-isopropylethylamine (0.02ml) followed by 2-bromo-5-chlorothiophene (0.016ml) in dry dioxan (0.25ml) were then added and the resultant solution was stirred at room temperature for 19h 10 and then heated at 80°C for 1h. The reaction was lowered to 60°C and maintained at this temperature for 20h. Evaporation of the cooled reaction mixture under a stream of nitrogen gave a residue that was purified by SPE (silica; using an OPTIX. Gradient elution [flow rate 10ml/min; fraction size 10ml; UV detector set at A™ax 254nm; 0 to 50% ethyl acetate -cyclohexane over 5min, followed by 50% to 100% ethyl acetate-cyclohexane for 11min and 15 then 100% ethyl acetate for 4min]) gave the title compound (0.0187g) as a clear oil. Using similar chemistry to that described for Example 61 Route 1, but selecting the appropriate starting materials the following were prepared: Example 62 20 5-Chloro-N-((3S)-1-fdS)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)-1-benzothiophene-2-sulfonamide Mass spectrum: Found: MH+ 472 H.p.l.c. (1) Rt2.9min 1H NMR (CDCI3):8 7.87(1 H, d), 7.86(1 H, m), 7.78(1 H, dm), 7.46(1 H, dd), 5.58(1 H, br.d), 25 5.02(1 H, q), 3.91 (1H, m), 3.69-3.44(9H, m), 3.34(1 H, m), 2.65(1 H, m), 2.10(1 H, m), 1.31(3H, d) ppm. Example 63 6-Chioro-N-((3S')-i-i('iS)-i-methvi-2-morphoiin-4-vi-2-oxoethvll-2-oxopvrrolidin-3-vl>-1-30 benzothiophene-2-sulfonamide Mass spectrum: Found: MH+ 472 H.p.l.c. (1) Rt2.96min 1H NMR (CDCI3):8 7.89(1 H, s), 7.85(1 H, br.m), 7.81 (1H, d), 7.44(1 H, dd), 5.46(1 H, br.d), 5.01 (1H, q), 3.90(1 H, m), 3.73-3.48(9H, m), 3.34(1 H, m), 2.67(1 H, m), 2.10(1 H, m), 1.31(3H, 35 d)ppm. Example 64 5-Chloro-3-methvl-N-i(3Sy-1-r(1sy-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlM-benzothiophene-2-sulfonamide 40 Mass spectrum: Found: MH+ 486 WO 02/100830 PCT/GB02/02721 64 H.p.l.c. (1) Rt 3.11min Example 65 3-Cvano-N4(3SV1-r(1S)-1-methvl-2-morphorm-4-vl-2-oxoethvn-2-oxopvnrolidin-3-5 vftbenzenesulfonamide Mass spectrum: Found: MH+ 407 H.p.l.c. (1) Rt2.4min Example 66 10 4-Cvano-N-f(3SV1-f(1SV1 -methvl-2-moroholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vllbenzenesulfonamide Mass spectrum: Found: MH+ 407 H.p.l.c. (1) Rt2.4min 15 Example 67 5-(5-Chloro-1.3.4-thiadiazol-2-vl)-N~f(3S)-1 -f( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvll-2- oxopvrrolidin-3-vl)thiophene-2-sulfonamide Mass spectrum: Found: MH+ 506 H.p.l.c. (1) Rt 2.82min 20 Example 68 5-Chloro-N-l(3S)-1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vl>thienor2.3-blpyridine-2-sulfonamide Mass spectrum: Found: MH+ 473 25 H.p.l.c. (1)Rt2.64min Example 69 5-Chloro-N-((3SV1-rf1S)-1-methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vi>thienoi3.2-blpyridine-2-sulfonamide 30 Mass spectrum: Found: MH+ 473 H.p.l.c. (1) Rt2.53min Example 70 6-Chloro-N-(('3S)-1 -f (1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopyrrolidin-3-vlV-N-(2-35 oxobutvn-1-benzothiophene-2-sulfonamide Using Example 63 and 1-bromo-2-butanone, and the synthetic procedure described for Example 50, the title compound was prepared. Mass spectrum: Found: MH+ 542 H.p.l.c. (1) Rt3.28min WO 02/100830 PCT/GB02/02721 65 Using similar chemistry, but selecting the appropriate starting materials following was prepared: Example 71 5 N2-r(6-Chloro-1 -benzothien-2-vl)sulfonvri-N2-lf3SV1 -\( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vllalvcinamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1)Rt 2.91 min 10 Example 72 5-Chloro-N-((3SV1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)-N-(2-oxobutvn-1-benzothiophene-2-sulfonamide Using Example 62 and 1-bromo-2-butanone, and the synthetic procedure described for Example 50, the title compound was prepared. 15 Mass spectrum: Found: MH+ 542 H.p.l.c. (1) Rt3.27min Using similar chemistry, but selecting the appropriate starting materials the following was prepared: 20 Example 73 N2-f(5-Chloro-1-benzothien-2-vl)sulfonvn-N2-fC3S)-1-fC1S)-1-methvl-2-morpholin-4-vl-2- oxoethvn-2-oxopvrrolidin-3-vl)glvcinamide Mass spectrum: Found: MH+ 529 H.p.l.c. (1)Rt2.85min 25 Example 74 6-Chloro-N-(f3SV1-r(1SV1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlV-N-phenvlnaphthalene-2-sulfonamide A mixture of Example 1 (0.0206g), phenylboronic acid (0.0162mg), copper (II) acetate 30 (0.016g), triethylamine 0.123ml) and powered 4A molecular sieves (dried, 0.1g) in dry DCM (0.5ml) was stirred at room temperature for 6 days. The reaction mixture was filtered using SPE (silica, eluting with 30% methanol in ethyl acetate). The organic fraction was concentrated under reduced pressure to give a brown residue that was purified by mass directed preparative h.p.l.c. to give the title compound (0.0062g) as a gum. 35 Mass spectrum: Found: MH+ 542 H.p.l.c. (1) Rt3.38min Using similar chemistry, but selecting the appropriate starting materials the following were prepared: 40 Example 75 WO 02/100830 PCT/GB02/02721 66 6-Chloro-N-(4-fluorophenv0-N-f(3Syi-r(1S>1-methvl-2-moroholin-4-vl-2-oxoethvn-2- oxopvrrolidin-3-vl>naphthalene-2-sulfonamide Mass spectrum: Found: MH+ 560 H.p.l.c. (1) Rt3.43min 5 Example 76 6-Chloro-N-((3S V1 -f( 1 SM-methvl-2-morpholin-4-vl-2-oxoethvH-2-oxopvrrolidin-3-vl}-N-pvridin-4-vlnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 543 10 H.p.l.c. (1) Rt 3.06min Example 77 6-Chloro-N-{(3SV1 -f(1 S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vll-N-pvridin-3-vlnaphthalene-2-sulfonamide 15 Mass spectrum: Found: MH+ 543 H.p.l.c. (1) Rt 3.10min Example 78 6-Chloro-N-f(3SV1-f(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)-N-thien-20 3-vlnaphthalene-2-sulfonamide Mass spectrum: Found: MH+ 548 H.p.l.c. (1) Rt3.38min Example 79 25 N2-r(6-Chloro-2-naphthvDsulfonvll-N2-((3SV1-{(1S1-2-f(2R.6Sy-2.6-dimethvlmorpholin-4-vn-1-methvl-2-oxoethvlV2-oxopvrrolidin-3-vl')glvcinamide Using Intermediate 26 and the procedure described for Example 1, the title compound was prepared. Mass spectrum: Found: mH+ 551 30 H.p.l.c. (1) Rt 3.02min Example 80 (E)-2-f3-Chloro-4-hvdroxvphenvl)-l\l-{(3S)-1 -f( 1 S)-1 -methyl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl)ethenesulfonamide 35 Sulphuryl chloride (0.036ml) was added dropwise to DMF (0.04ml) at 0°C and the mixture was stirred at room temperature for 2h. Intermediate 53 (0.102g) in cyclohexane (0.2ml) was added in one portion and the resultant mixture was heated at 90°C for 6h. The cooled reaction mixture was poured onto ice and extracted with DCM. The combined organic extracts were dried (over magnesium sulphate) and concentrated under reduced pressure to 40 give a brown oil which was treated with sulphuryl chloride (0.035ml) and triphenyl phosphine WO 02/100830 PCT/GB02/02721 67 (0.103g) in dry DCM (ca. 0.5ml). After stirring for 3h at room temperature, the mixture was filtered through a SPE silica cartridge preconditioned with cyclohexane. Elution with ethyl acetate gave, after concentration under reduced pressure, an orange-brown solid which was stirred with Intermediate 40 (0.04g), 4-dimethylaminopyridine (0.021g), N,N-di-5 isopropylethylamine (0.059ml) in dry DCM (1ml). After stirring for 3 days at room temperature under nitrogen, the mixture was concentrated under reduced pressure. The residue was purified initially using SPE (silica) followed by mass directed preparative h.p.l.c. to give the title compound (0.0035g) as a white solid. Mass spectrum: Found: MH*458 10 H.p.l.c. (1)Rt2.58min Example 81 (E)-2-(4-Chloro-3-hvdroxyphenvl)-N-f(3S)-1 -f( 1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvll-2-oxopvrrolidin-3-vltethenesulfonamide 15 To a solution of Intermediate 55 (0.0078g) in THF (0.3ml) at -78°C under nitrogen, tetra n-butylammonium fluoride (1M in THF, 0.014ml) was added. The mixture was allowed to warm to room temperature over 3 days and then concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.0043g) as a clear film. 20 Mass spectrum: Found: MH+ 458 H.p.l.c. (1)Rt2.67min Example 82 6-Chloro-N4(3SV1-r(1S>1-methvl-2-morphorin-4-v!-2-oxoethvn-2-oxopvrrolidin-3-vl)-N-(2-25 morpholin-4-vlethvl)naphthalene-2-sulfonamide formate Example 1 (0.05g) was dissolved in DMF (1ml) and treated with chloroethylmorpholine hydrochloride (0.062g) and potassium carbonate (0.093g), and stirred at 40'C for 2h. The mixture was then heated at 80'C for 8h, cooled and treated with ethyl acetate and water. The organic exiraci was dried (over magnesium suiphate) and concentrated under reduced 30 pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.018g) as a white solid. Mass spectrum: Found: MH+ 579 H.p.l.c. (1) Rt2.56min Using similar chemistry, but selecting the appropriate starting materials the following were 35 prepared: Example 83 6-Chloro-N-f(3SV-1 -[(1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopyrrolidin-3-vl)-IM-(2-pyrrolidin-1 -vlethvhnaphthalene-2-sulfonamide formate 40 Mass spectrum: Found: MH+ 563 WO 02/100830 PCT/GB02/02721 68 H.p.l.c. (1) Rt2.58min Example 84 6-Chloro-N-r2-fdimethvlamino)ethvn-N-l(3S)-1-r(1S)-1-methvl-2-morpholin-4-vl-2-oxoethvn-5 2-oxopvrrolidin-3-vl}naphthalene-2-sulfonamide formate Mass spectrum: Found: MH+ 537 H.p.l.c. (1) Rt2.53min Example 85 10 N-r2-(r(6-Chloro-2-naphthv0sulfonvll((3Syi-r(1syi-methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vl>amino)ethvnacetamide Mass spectrum: Found: MH+ 551 H.p.l.c. (1) Rt2.91min 15 Example 86 5-Chloro-N-((3SM -K1 S)-1 -methvl-2-morpholin-4-vl-2-oxoethvn-2-oxopvrrolidin-3-vlV-1 H-indole-2-sulfonamide Intermediate 33 (0.011g) was dissolved in 1:1 TFA / DCM (0.5ml) and allowed to stand at room temperature for 1h. The mixture was concentrated under reduced pressure and the 20 residue partitioned between saturated aqueous sodium bicarbonate and DCM. The separated organic phase was dried (over magnesium sulphate) and concentrated under a stream of nitrogen to give the title compound (0.0082g) as white solid. Mass spectrum: Found: MH+ 455 H.p.l.c. (1) Rt2.97min 25 Example 87 6-Chloro-N4(3SV-1 -I'd S)-1 -methvl-2-morpholin-4-vl-2-oxoethvfl-2-oxopyrrolidin-3-vl)-1.3-benzothiazole-2-sulfonamide intermediate 58 (O.lg) was stirred at room temperature in anhydrous acetone (3ml) and 5% 30 aqueous potassium permanganate (1.35ml) for 3h, after which additional acetone (3ml) and 5% aqueous potassium permanganate (1.35ml) were added. The reaction mixture was stirred for a further 18h and filtered through Celite™. The filtrate was concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c to give the title compound (0.0062g) as a white solid. 35 Mass spectrum: Found: MH+ 473 H.p.l.c. (1) Rt2.98min Example 88 6-Chloro-N-((3Sy-1-rdSV1-methvl-2-(2-methvlmorpholin-4-vD-2-oxoethvn-2-oxopvrrolidin-3-40 vllnaphthalene-2-sulfonamide WO 02/100830 PCT/GB02/02721 69 To polymer N-cyclohexylcarbodiimide-N'-propyloxymethyl polystyrene (0.038g) in an Alltech™ tube was added a solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.007g) in DCM (0.9ml) followed by 2-methylmorpholine (0.004g) in DMF (0.1ml) and N,N-diisopropylethylamine (0.006ml). The mixture was shaken 5 at room temperature for 4 days. The tube was drained, the filtrate collected and the resin washed with DCM. The combined DCM solutions were concentrated under reduced pressure and the residue purified by mass directed preparative h.p.l.c. to give the title compound (0.0038g) as an off-white solid. Mass spectrum: Found: MH+ 480 10 H.p.l.c. (1)Rt3.17min Example 89 (EV2-(5-Chlorothien-2-vlVN-methvl-N-((3S)-1-[(1SV1-methvl-2-morpholin-4-vl-2-oxoethvl1-2-oxopvrrolidin-3-vllethenesulfonamide 15 Sodium hydride (60% dispersion in oil, 0.011g) was added to trimethysulphonium iodide (0.059g) in dimethylsulphoxide (2ml) between 5-10'C, and the resultant mixture was stirred at room temperature for 30min. Example 61 (0.1 g) in dry THF (2ml) was added between 5-10'C, and the solution stirred at room temperature for 2.25h, at 50'C for 70h, cooled to room temperature and poured onto ice/water. The aqueous mixture was extracted with ethyl 20 acetate and the combined, dried (over magnesium sulphate) organic extracts were concentrated under reduced pressure. The residue was purified using mass directed preparative h.p.l.c. to give the title compound (0.038g) as a colourless oil. Mass spectrum: Found: MH+ 462 H.p.l.c. (1) Rt 2.82min 25 Example 90 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-(4-morpholinyl)-2-oxoethyl]-2-oxopyrrolidinyl}thieno[3,2-b]pyridine-2-sulfonamide The title compound was similarly prepared using Intermediate 40 and 6-chlorothieno[3,2-30 f>]pyridine-2-sulfonyl chloride*, and the synthetic procedure decribed for Example 386 (Route 1). Mass spectrum: Found: MH+ 473 H.p.l.c. (I) Rt 2.61 min 35 'Prepared according to the procedure described in US6281227. References 40 WO 02/100830 PCT/GB02/02721 70 1. Klimkowski, Valentine Joseph; Kyle, Jeffrey Alan; Masters, John Joseph; Wiley, Michael Robert. PCT Int. Appl. (2000), WO 0039092. 2. . Choi-Siedeski, Yong Mi; Pauls, Heinz W.; Barton, Jeffrey N.; Ewing, William R; Green, Daniel M.; Becker, Michael R; Gong, Yong; Levell, Julian. PCT Int. Appl. (1999), 5 WO 9962904. In vitro assay for inhibition of Factor Xa Compounds of the present invention were tested for their Factor Xa inhibitory activity as determined in vitro by their ability to inhibit human Factor Xa in a chromogenic assay, using 10 N-a-benzyloxycarbonyl-D-Arg-Gly-Arg-p-nitroanilide as the chromogenic substrate. Compounds were diluted from a 10mM stock solution in dimethylsulfoxide at appropriate concentrations. Assay was performed at room temperature using buffer consisting of: 50mM Tris-HCI, 150mM NaCI, 5mM CaCI2, pH 7.4. containing human Factor Xa (final conc. Of 0.0015 U.ml-1). Compound and enzyme were preincubated for 15min prior to addition of the 15 substrate (final conc. of 200|jM). The reaction was stopped after 30min with the addition of soybean trypsin inhibitor or H-D-PHE-PRO-ARG-Chloromethylketone. BioTek EL340 or Tecan SpectraFluor Plus plate readers were used to monitor the absorbance at 405nM. To obtain 1C50 values the data were analysed using ActivityBase® and XLfit®. 20 All of the synthetic Example compounds tested (Examples 1-52,54-89) exhibited IC50 values of less than 60(j.M. Preferably compounds have an IC50 value of less than 2\iM, more preferably compounds have an IC50 value of less than 0.1 |iM. 25 Measurement of prothrombin time (PT) - Test 1 Blood was collected into a sodium citrate solution (ratio 9:1) to give a final concentration of 0.38% citrate. Plasma was generated by centrifugation of citrated blood samples at 1200 xg for 20min at 4°C. The PT test was performed at 37~C in piastic cuvettes containing a magnetic ball bearing. 30 50)jL of citrated plasma and either 25pL of 2.8% DMSO for control or 25[jL of test compound (dissolved in DMSO and diluted in water and 2.8% DMSO to give 0.4% DMSO final in assay) at a concentration of 7-times the final desired concentration was pippetted into each cuvette. This mixture was incubated for 1min at 37°C before adding 100pL of thromboplastin mixture (comprising lyophilised rabbit thromboplastin and calcium chloride 35 which was reconstituted in distilled water as per manufacturer's [Sigma] instructions). On addition of the thromboplastin mixture, the timer was automatically started and continued until the plasma clotted. The time to clotting was recorded (normal range for human plasma is 10-13 seconds). 40 Method for measurement of prothrombin time (PT) - Test 2 WO 02/100830 PCT/GB02/02721 71 Blood is collected into a sodium citrate solution (ratio 9:1) to give a final concentration of 0.38% citrate. Plasma is generated by centrifugation of citrated blood samples at 1200 xg for 20min at 4°C. 5 The PT test is performed at 37°C in plastic cassettes and using a MCA210 Microsample Coagulation Analyzer (Bio/Data Corporation). For assay, 25 ul of plasma containing test compound at concentrations ranging from 0.1 to 100 uM (made from a 1 mM stock solution in 10% DMSO and plasma) and 25 ul of Thromboplastin C Plus (Dade Berhing) are automatically injected into the cassette. Upon addition of the Thromboplastin C Plus, the 10 instrument determines and records the time to clot (normal range for human plasma is 10-13 seconds). General purification and analytical methods Analytical HPLC was conducted on a Supelcosil LCABZ+PLUS column (3pm, 3.3cm x 15 4.6mm ID) eluting with 0.1% HC02H and 0.01 M ammonium acetate in water (solvent A), and 95% acetonitrile and 0.05% HC02H in water (solvent B), using the following elution gradient 0-0.7 minutes 0%B, 0.7-4.2 minutes 0->100%B, 4.2-5.3 minutes 100%B, 5.3-5.5 minutes 100—>0%B at a flow rate of 3 ml/minutes (System 1). The mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using electrospray positive ionisation 20 [(ES+ve to give MH+ and M(NH4)+ molecular ions] or electrospray negative ionisation [(ES-ve to give (M-H)" molecular ion] modes. LC/MS System (3) Method 2 was conducted on a Waters Xtera RP18 column (3pm, 15cm x 2.1mm ID) eluting 25 with solvent A (0.1% HC02H and water) and solvent B (100% acetonitrile, 0.1% HC02H and reserpine 2.5|jgml-1) at 20°C. The following elution gradient was ran: 0-2.0 minutes 0% B; 2.0-18.0 minutes 0-100% B; 18.0-20.0 minutes 100%B; 20.0-22.0 minutes 100-0%B; 22.0-30.0 minutes 0%B, at a flow rate of 0.4 ml/minutes. The mass spectra (MS) were recorded on a Micromass QTOF 2 spectromeier using eiectrospray positive ionisation 30 [ES+ve to give MH+]. Note: The number given in brackets in the Examples and Intermediates above, e.g. H.p.l.c. (1), specifies the LC/MS method used. 35 1H nmr spectra were recorded using a Bruker DPX 400MHz spectrometer using tetramethylsilane as the external standard. Biotage™ chromatography refers to purification carried out using equipment sold by Dyax Corporation (either the Flash 40i or Flash 150i) and cartridges pre-packed with KPSil. Mass directed autoprep refers to methods where the material was purified by high 40 performance liquid chromatography on a HPLCABZ+ 5pm column (5cm x 10mm i.d.) with </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 02/100830 PCT/GB02/02721 72 0.1% HC02H in water and 95% MeCN, 5% water (0.5% HC02H) utilising the following gradient elution conditions: 0-1.0 minutes 5%B, 1.0-8.0 minutes 5—>30%B, 8.0-8.9 minutes 30%B, 8.9-9.0 minutes 30—>95%B, 9.0-9.9 minutes 95%B, 9.9-10 minutes 95-»0%B at a flow rate of 8ml minutes"1 (System 2). The Gilson 202-fraction collector was triggered by a 5 VG Platform Mass Spectrometer on detecting the mass of interest. Hydrpophobic frits refers to filtration tubes sold by Whatman. SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd. TLC (thin layer chromatography) refers to the use of TLC plates sold by Merck coated with 10 silica gel 60 F254. 15 73 Claims

1. A compound of formula (I): B O (I) 5 wherein: R1 represents hydrogen, -Ci_6alkyl, -C^alkenyl, -C2-3alkylNRbRc, -C2-3alkylNHCORb, phenyl or a 5- or 6- membered aromatic heterocyclic group, the phenyl or 5- or 6- membered aromatic heterocyclic group being optionally substituted by halogen, or R1 represents a 10 group X-W, wherein X represents -C^alkylene- and W represents -CN, -C02H, -CONRbRc, -COC-i-ealkyl, -C02C1.6alkyl, phenyl or 5- or 6- membered aromatic or non-aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one or more substitutents selected from: -C^alkyl, -C^alkoxy, -CwalkylOH, halogen, -CN, -CF3, -NH2, -C02H and - R2 and R3 independently represent hydrogen, -C^alkyl or -CF3 with the proviso that one of R2 and R3 is -C^alkyl or -CF3 and the other is hydrogen; 20 Rb and Rc independently represent hydrogen or -Chalky!; A represents a group selected from: 15 OH; ii':t i> •" s r' -"r,Qrty 2 3 JUM 2005 WO 02/100830 PCT/GBO2/02721 74 -CN \ // "(CM)alkenylene- // -< Z represents one or two optional substituents independently selected from halogen and OH, W represents an optional substituent -Chalky!, 5 alk represents C2.3alkylene or C^alkenylene, T represents a heteroatom selected from O, S or N; B represents one or more optional substituents on ring carbon atoms selected from: (i) one or more substituents selected from -CF3, -F, -C02H, -C^alkyl, -C^alkylOH, -(Ci-10 3alkyl)NRbRc, -(C(Walkyl)CONRbRc and -(C0^alkyl)CO2C^alkyi, -CONHC2.3alkylOH, -CH2NHC2.3aikylOH, -C^OC^alkyl and -CH2S02Ci_3alkyl; (ii) a group -Y-R®, Y represents -C^alkylene-, -CO-, -C^alkylNH-, -C^alkylNHCO-, -C^alkylNHSO^, -CH2NHS02CH2- or a direct link, 15 Re represents phenyl, a 5- or 6- membered cycloalkyi or a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -C^alkyl, -C^alkoxy, -C-i-3alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; or (iii) a second ring Rf which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 20 5- or 6- membered cycloalkyi group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: -C^alkyl, -C^alkoxy, -Ci. 3alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; and pharmaceuticaliy acceptable derivatives thereof. 25 2. A compound as claimed in claim 1 having the formula (la): 75 R: R3 O (la) wherein: 5 R1 represents hydrogen, -Chalky!, -C2-6alkenyl or a group X-W, wherein X represents -Ci. 3alkylene- and W represents -CN, -C02H, -CONRbR°, -COCvealkyl, -CO^A.ealkyl, phenyl or 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, the phenyl or aromatic heterocyclic group being optionally substituted by one 10 or more substitutents selected from: -Ci-3alkyl, -Cv3aIkoxy, -Ct.3alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; R2 and R3 independently represent hydrogen, -ChalkyI or -CF3 with the proviso that when one of R2 and R3 is -Chalky) or -CF3, the other is hydrogen; 15 Rb and Rc independently represent hydrogen or -C^alkyl; A represents a group selected from: Z represents an optional substituent halogen, WO 02/100830 PCT/GB02/02721 76 alk represents alkylene or alkenylene, T represents a heteroatom selected from S or N; B represents one or more optional substituents on ring carbon atoms selected from: (i) one 5 or more substituents selected from -CF3, -F, =0, -C02H, -Chalky!, -C^alkylOH, -(ci-3alkyl)NRbRc, -(C0^alkyl)CONRbRc and -(C(Malkyl)C02C^alkyl; (ii) a group -Y-R®, Y represents -C^alkylene-, -CO-, -C^alkylNH-, -C^alkylNHCO-, -C^alkylNHSOa-, -CH2NHS02CH2- or a direct link, 10 Re represents phenyl, a 5- or 6- membered cycloalkyi or a 5- or 6- membered heterocycle containing at least one heteroatom selected from O, N or S, each of which is optionally substituted by one or more substituents selected from: -C^alkyl, -C^alkoxy, -C^alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; or (iii) a second ring Rf which is fused to the heterocyclic ring, wherein Rf represents phenyl, a 15 5- or 6- membered cycloalkyi group or a 5- or 6- membered aromatic heterocyclic group containing at least one heteroatom selected from O, N or S, and the fused bicyclic group is optionally substituted by one or more substituents selected from: -Chalky!, -C^alkoxy, -Ci. 3alkylOH, halogen, -CN, -CF3, -NH2, -C02H and -OH; and pharmaceuticaliy acceptable salts and solvates thereof. 3. A compound as claimed in claim 1 wherein R1 represents hydrogen, -C^alkyl, -Ca. 6alkenyl, -C2.3alkylNRbRc, -C2-3alkylNHC0Rb, phenyl or a 5- or 6- membered aromatic heterocycle, or R1 represents a group X-W wherein X represents -C^alkylene- and W represents -CN, -C02H, -CONRbRc, -COC^alkyl, -C02C1.6alkyl, or a 5- or 6- membered 25 aromatic or nonaromatic heterocyclic group containing at least one heteroatom selected from O, N or S. 4. A compound as claimed in any one of claims 1-3 wherein R2 represents -Chalky! or 5. A compound as claimed in any one of claims 1-4 wherein R3 represents -Chalky! or 6. A compound as claimed in any one of claims 1-5. wherein B represents hydrogen or a 35 substituent selected from -C^alkyl, -CONHCH3, -CONHCH2CH(OH)CH3, -CH2NH(QH3)2, -CH2OCH3, -CH2S02CH3, -CH2NHCH2CH(OH)CH3> 20 nyutoyen. 30 hydrogen. / \ WO 02/100830 PCT/GB02/02721 77 7. A compound as claimed in any one of claims 1-6 wherein B represents hydrogen. 8. A compound as claimed in any one of claims 1-7 wherein A represents a group selected from 9. A compound as claimed in claim 1 selected from: (E)-2-(4-Chlorophenyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 10 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yI-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-2,2'-bithiophene-5-sulfonamide, N2-{[(E)-2-(4-Chlorophenyl)ethenyl]sulfonyl}-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-15 oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N2-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N2-{(3S)-1-[(1 S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 5'-Chloro-N-(cyanomethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morphorin-4-yl-2-oxoethyi]-2-oxopyrrolidin-3-yl}-2,2'-bithiophene-5-sulfonamide, 20 Methyl N-[(5'-chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, 5'-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin~3-yl}-N-(2-oxobutyl)-2,2'-bithiophene-5-sulfonamide, N-[(5'-Chloro-2,2'-bithien-5-yl)sulfonyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-25 oxoethyi]-2-oxopyrrolidin-3-yl}glycine, (E)-2-(4-Chlorophenyl)-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, (E)-2-(4-Chlorophenyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)ethenesulfonamide, 30 Methyl N-{[(E)-2-(4-chlorophenyl)ethenyl]sulfonyl}-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl>glycinateI 6-Chloro-N-(3-furylmethyI)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-35 (pyridin-3-ylmethyl)naphthalene-2-sulfonamide formate, WO

02/100830 PCT/GB02/02721 78 6-Chloro-N-ethyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)naphthalene-2-sulfonamide, 5 N-2-[(6-Chloro-2-naphthyl)sulfonyl]-N-2-{(3S)-1 -[(1 S)-1 -methy!-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, 6-Chloro-N-(2-furylmethyl)-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyO-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-{(3S)-1 -[(1 S)-1 -methy)-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(1,3-10 thiazol-2-ylmethyl)naphthalene-2-sulfonamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmo.rpholiri-4-yl]- 1-methyl-2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-[(2-methyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide, 15 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(pyridin-4-ylmethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-(cyanomethyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-20 oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-methyl-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, 6-Chloro-N-(3,3-dimethyl-2-oxobutyl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]- 2-oxopyrrolidin-3-yl}naphthatene-2-sulfonamide, 25 N-Allyl-6-chloro-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}naphthalene-2-sulfonamide, Methyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2- oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, te/t-Butyl N-[(6-chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-30 oxoethyl]-2-oxopyrrolidin-3-yl}glycinate, N-[(6-Chloro-2-naphthyl)sulfonyl]-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}g lycine, (E)-2-(5-Chlorothien-2-yl)-N-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide, 35 6-Chloro-N-{(3S)-H(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-oxobutyl)-1-benzothiophene-2-sulforiamide, N2-[(6-Chloro-1 -benzothien-2-yl)sulfonyl]-N2-{(3S)-1 -[(1 S)-1 -methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}glycinamide, N2-[(6-Chloro-2-naphthyl)sulfonyl]-N2-((3S)-1-{(1S)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-40 1 -methyl~2-oxoethyl}-2-oxopyrrolidin-3-yl)glycinamide, 79 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl~2~oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-morpholin-4-ylethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}-N-(2-pyrrolidin-1-yIethyl)naphthalene-2-sulfonamide formate, 6-Chloro-N-[2-(dimethylamino)ethyl]-N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yI}naphthalene-2-sulfonamide formate, and N-[2-([(6-Chloro-2-naphthyl)sulfonyl]{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}amino)ethyl]acetamide. 10. A compound as claimed in claim 1 and pharmaceuticaliy acceptable salts and solvates thereof. 11. (E)-2-(5-Chlorothien-2-yl)-N-{(35)-1-[(15)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl} ethane sulphonamide and pharmaceuticaliy acceptable solvates thereof. 12. A pharmaceutical composition comprising a compound according to any one of claims 1-11 together with a pharmaceutical carrier and/or excipient. 13. Use of a compound according to any one of claims 1-11 for the manufacture of a medicament for the treatment of a patient suffering from a condition susceptible to amelioration by a Factor Xa inhibitor. 14 Use of a compound as claimed in claim 13 wherein the condition susceptible to amelioration by a Factor Xa inhibitor is selected from coronary thrombosis, pulmonary embolism, deep vein thrombosis and the prevention of thromboembolic events associated with atrial fibrillation. 15. A process for preparing a compound of formula (I) which comprises: (a) reacting a compound of formula (II) with a compound of formula (111): (") H ,N, -b (NO "O 80 OR: (b) reacting a compound of formula (XV) with a compound of formula (VI): H /A .N—Sv //\\ O O (XV) o r1—x (VI) wherein X is a halogen atom; OR: (c) reacting a compound of formula (XVI) with a compound of formula (VIII): R \ N—H (XVI) TXA o o wherein T represents a halide. (VIII) jS&al t'rocprty Office 0! I 5 Jy 16. A compound of formula (I) when prepared by a process as claimed in claim 15. 17. A compound of formula (I) as claimed in claims 1 or 16 substantially as herein described with reference to any Example thereof. 18. A pharmaceutical composition as claimed in claim 12 substantially as herein described with reference to any Example thereof. 19. A use as claimed in claim 13 substantially as herein described with reference to any Example thereof. 20. A process as claimed in claim 15 substantially as herein described with reference to any Example thereof. END OF CLAIMS </div>